PROPOSAL FOR THE INCLUSION OF ANTI-EMETIC MEDICATIONS (FOR CHILDREN) IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES Marc Bevan, Kent Johnson, Elizabeth Seil and Jane Robertson Discipline of Clinical Pharmacology School of Medicine and Public Health Faculty of Health University of Newcastle Level 5, Clinical Sciences Building, NM2 Calvary Mater Hospital Edith Street, Waratah, 2298 New South Wales AUSTRALIA Tel +61-02-49211726 Fax + 61-02-49602088 WHO EML – Anti-emetics – January 2009 1. Summary statement of the proposal Anti-emetic medications (anti-histamines, dopamine antagonists, serotonin 5-HT3 antagonists, steroids and anti-cholinergics) are proposed for inclusion in the World Health Organization (WHO) Model List of Essential Medicines for the management of postoperative nausea and vomiting in children. 2. Name of focal point in WHO submitting or supporting the application 3. Name of the organisation preparing the application Discipline of Clinical Pharmacology, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Level 5, Clinical Sciences Building, NM2, Calvary Mater Hospital, Edith Street, Waratah, 2298, New South Wales, Australia. 4. Treatments reviewed in the proposal The proposal reviews relevant data regarding the use of five classes of anti-emetic medications for the management of postoperative nausea and vomiting in children: o Anti-histamines (e.g. cyclizine, dimenhydrinate, promethazine) o Dopamine antagonists (e.g. droperidol, metoclopramide, perphenazine) o Serotonin 5-HT3 antagonists (e.g. granisetron, ondansetron, tropisetron) o Steroids (e.g. dexamethasone) o Anti-cholinergics (e.g. hyoscine) It should be noted that two treatments (promethazine and metoclopramide) are currently listed on the WHO Model List of Essential Medicines as anti-emetic medications for children (WHO, 2007). Other treatments are also available for the management of postoperative nausea and vomiting including: benzodiazepines, neurokinin NK1 antagonists, opioid antagonists, acupuncture, ephedrine, propofol and ginger. However assessment of these treatments was beyond the scope of the current review. 5. Information supporting the public health relevance 5.1 Disease burden Postoperative nausea and vomiting are common complications of surgery for both children and adults. In addition to being an unpleasant sensation, postoperative nausea and vomiting can cause further complications in patients. Severe vomiting can stress wounds, induces body electrolyte imbalances, cause bleeding and lead to the pulmonary aspiration of gastric contents. Even mild symptoms may delay hospital discharge, reduce patient/guardian satisfaction and lead to the increased use of other medical resources (Rose and Watcha 1999). The overall incidence of postoperative vomiting in children has been estimated to be between 10-40%; while the incidence of nausea is more uncertain, as young children may 1 WHO EML – Anti-emetics – January 2009 be unable to effectively communicate the presence and severity of nausea. In general, the incidence of postoperative vomiting in children is estimated to be twice the incidence for both nausea and vomiting combined in adults (Kovac 2007). A number of risk factors have been associated with an increased incidence of post- operative vomiting in children including: duration of surgery > 30 minutes; age > 3 years, strabismus surgery, and a history of postoperative vomiting in the patient, parent or sibling (Gan et al 2007). 5.2 Treatment guidelines A simplified treatment algorithm for the management of postoperative nausea and vomiting in adults and children is shown in Figure 1 (adapted from the SAMBA guidelines, Gan et al 2007). It should be noted that not all of the therapeutic options available for adults are recommended for children (recommended treatments for children from the SAMBA guidelines are summarised in Table 1). Table 1: Anti-emetic treatments recommended for the management of postoperative nausea and vomiting in children Treatment Recommended dose Monotherapy Dexamethasone 150 mcg/kg i.v. up to 5 mg Dimenhydrinate 0.5 mg/kg i.v. up to 25 mg Dolasetron 350 mcg/kg i.v. up to 12.5 mg Droperidola 10–15 mcg/kg i.v. up to 1.25 mg Granisetron 40 mcg/kg i.v. up to 0.6 mg Ondansetron 50–100 mcg/kg i.v. up to 4 mg Perphenazine 70 mcg/kg i.v. up to 5 mg Tropisetron 0.1 mg/kg i.v. up to 2 mg Combination therapiesb Ondansetron, 0.05 mg/kg i.v. + dexamethasone, 0.015 mg/kg i.v. Ondansetron, 0.1 mg/kg i.v. + droperidol, 0.015 mg/kg i.v. Tropisetron, 0.1 mg/kg i.v. + dexamethasone, 0.5 mg/kg i.v. Source: Treatment guidelines published by Gan et al (2007). a An FDA “black box” warning has been applied to droperidol due to the risk of cardiovascular adverse events. It is recommended that droperidol only be used if other therapies have failed and patient is being admitted to hospital. b The same maximum dose applies to treatments used as either a monotherapy or as a component of combination therapy Current guidelines do not recommend the use of metoclopramide or promethazine in the treatment of post-operative nausea and vomiting in children (Gan et al 2007). 2 WHO EML – Anti-emetics – January 2009 Figure 1: Clinical pathway for the management of postoperative nausea and vomiting Abbreviations: PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RF, risk factor Note: Treatment algorithm modified from the algorithm published by Gan et al (2007). Treatment options: If prophylaxis fails or was not received: use anti-emetic from different class than prophylactic agent. Re-administer only if > 6 hours after post-anaesthesia care unit; do not re-administer dexamethasone or hyoscine. Use droperidol in children only if other therapy has failed and patient is being admitted to hospital 3 WHO EML – Anti-emetics – January 2009 6. Identification of clinical evidence Searches were conducted in the databases indicated in Table 2. The search terms included the following: o Postoperative nausea and vomiting, and o Anti-emetic, alizapride, betamethasone, chlorpromazine, cimetidine, cinnarizine, clebopride, cyclizine, dexamethasone, dimenhydrinate, dixyrazine, dolasetron, domperidone, droperidol, famotidine, granisetron, haloperidol, hyoscine, itasetron, meclozine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, prednisolone, prochlorperazine, promethazine, ramosetron, ranitidine, sulpiride, tiapride, trifluoperazine, tropisetron. Table 2: Electronic databases searched during the review of anti-emetics Database Date Searched MEDLINE and EMBASEa 21 January 2009 Cochrane library 21 January 2009 PREMEDLINEb 21 January 2009 a Using the EMBASE.com interface b Using the PubMed interface Comprehensive details of the literature searches performed using the electronic databases are presented in Appendix A. The citation lists of included studies were searched to identify any additional studies. Studies were included if they were systematic reviews evaluating the effectiveness of anti-emetic medications for the management of post-operative nausea and vomiting in children. Systematic reviews in languages other than English were excluded. 7. Summary of available comparative data 7.1 Summary of available efficacy data The literature search identified 25 systematic reviews that met the inclusion criteria: o Seven reviews evaluating the effectiveness of anti-emetics in the prevention of postoperative nausea and vomiting in children (Bolton et al 2006, Engelman et al 2008, Goldman et al 2000, Lim et al 1999, Steward et al 2001, Steward et al 2003, Tramer et al 1995). o Seven reviews evaluating the effectiveness of anti-emetics in the prevention of postoperative nausea and vomiting in both adults and children and provided a separate analysis of children studies (Domino et al 1999, Figueredo & Canosa 1998, Henzi et al 1999, Henzi et al 2000, Henzi et al 2000b, Kranke et al 2002, Warren et al 2008). o Six reviews evaluating the effectiveness of anti-emetics in the prevention of postoperative nausea and vomiting in both adults and children but did not provide a separate analysis of children studies. While these systematic reviews were 4 WHO EML – Anti-emetics – January 2009 included in the current review they only provided supportive evidence for evaluating the efficacy of anti-emetic medications in children (Carlisle & Stevenson 2006, Eberhardt et al 2000, Habib et al 2004, Kranke et al 2002b, Leslie & Gan 2006, Tramer et al 1997b). o Two reviews evaluating the effectiveness of anti-emetics in the treatment of established postoperative nausea and vomiting in both adults and children. While these systematic reviews were included in the current review they only provided supportive evidence for evaluating the efficacy of anti-emetic medications in children (Kazemi et al 2001, Tramer et al 1997). o Three reviews meeting inclusion criteria were later excluded for the following reasons; methodology review examining the impact of a single dominating centre on meta-analyses (Kranke et al 2001); methodology review examining the impact of duplicate publications on meta-analyses (Tramer et al 1997c); a review of systematic reviews for postoperative vomiting (also included a systematic review of postoperative analgesia) (McQuay et al 1998) Details of the included systematic reviews are presented in Appendix B. A brief overview of the available evidence in children relating to each of the five classes of anti-emetic medications under review (anti-histamines, dopamine antagonists, serotonin 5-HT3 antagonists, steroids