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 and anti-cholinergics) is presented in Tables 3-14.

In general, four main statistical measures were used in the systematic reviews including: o relative benefit (RB), relative likelihood of not having the adverse outcome compared to the control (i.e. RB > 1 indicates a positive treatment effect) o relative risk (RR), relative likelihood of having the adverse outcome compared to the control (i.e. RR < 1 indicates a positive treatment effect) o odds ratio (OR), measure of the odds of an adverse event happening compared to the odds of the same event not happening (i.e. OR < 1 indicates a positive treatment effect) o number needed to treat (NNT), the number of patients that need to be treated for one extra patient to receive benefit. NNT was not reported in the current review as this measure is dependent on the prevalence of the target condition in any given population.

However, it should be noted that three reviews by Figueredo & Canosa (1998), Henzi et al (2000b) and Tramer et al (1995), reported OR and RR based on the number of patients not experiencing the adverse outcome (i.e. the reverse of the description outlined above).

Because of the subtle differences in the statistical measures used amongst the systematic reviews a statement has been included for each review indicating the direction of a positive treatment effect.

5 WHO EML – Anti-emetics – January 2009

Anti-histamines

Table 3: Results of systematic reviews assessing the effectiveness of prophylactic dimenhydrinate in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - dimenhydrinate vs. placebo (1 study) [OR 0.84, 95% CI 0.20–3.65] Kranke (2002) [RB > 1 indicates a positive treatment effect] PONV up to 48 hours: - dimenhydrinate 0.5–2.2 mg/kg i.v./i.m. vs. placebo (3 studies) [RB 1.8, 95% CI 1.31–2.47] - dimenhydrinate 2–3 mg/kg rectal dose vs. placebo (2 studies) [RB 1.7, 95% CI 1.16–2.53] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RB, relative benefit. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that dimenhydrinate may be more effective than placebo in reducing postoperative nausea and/or vomiting.

Dopamine antagonists

Table 4: Results of systematic reviews assessing the effectiveness of prophylactic metoclopramide in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - metoclopramide vs placebo (4 studies) [OR 0.51, 95% CI 0.34–0.77] Lim (1999) [RR < 1 indicates a positive treatment effect] POV up to 24 hours: - ondansetron vs. metoclopramide (8 studies) [RR 0.56, 95% CI 0.44–0.71] Tramer (1995) [OR > 1 indicates a positive treatment effect] (strabismus surgery) POV up to 6 hours: - metoclopramide 0.10 mg/kg vs. placebo (1 study) [OR 3.9, 95% CI 0.7–20.9] - metoclopramide 0.15 mg/kg vs. placebo (3 studies) [OR 2.8, 95% CI 1.7–4.6] - metoclopramide 0.25 mg/kg vs. placebo (2 studies) [OR 5.0, 95% CI 2.4–10.3] POV up to 48 hours: - metoclopramide 0.15 mg/kg vs. placebo (3 studies) [OR 6.6, 95% CI 1.7–25.1] - metoclopramide 0.25 mg/kg vs. placebo (2 studies) [OR 1.7, 95% CI 0.6–4.8] Domino (1999) [OR < 1 indicates a positive treatment effect] Any POV: - ondansetron vs. metoclopramide (6 studies) [OR 0.33, 95% CI 0.27–0.39] - droperidol vs metoclopramide (7 studies) [OR 0.63, 95% CI 0.36–1.10] Henzi (1999) [RB > 1 indicates a positive treatment effect] POV up to 6 hours: - metoclopramide 0.10 mg/kg i.v. vs. placebo (1 study) [RB 1.17, 95% CI 0.97–1.41] - metoclopramide 0.12 mg/kg i.v. vs. placebo (1 study) [RB 0.83, 95% CI 0.62–1.12] - metoclopramide 0.15 mg/kg i.v. vs. placebo (3 studies) [RB 1.71, 95% CI 1.33–2.19] - metoclopramide 0.20 mg/kg i.v. vs. placebo (1 study) [RB 1.11, 95% CI 0.80–1.54] - metoclopramide 0.25 mg/kg i.v. vs. placebo (7 studies) [RB 1.44, 95% CI 1.11–1.87] - metoclopramide 0.50 mg/kg i.v. vs. placebo (2 studies) [RB 1.32, 95% CI 0.89–1.96] PON up to 6 hours: - metoclopramide 0.12 mg/kg i.v. vs. placebo (1 study) [RB 1.00, 95% CI 0.81–1.23]

6 WHO EML – Anti-emetics – January 2009

Results - metoclopramide 0.20 mg/kg i.v. vs. placebo (1 study) [RB 1.25, 95% CI 0.81–1.94] POV up to 48 hours: - metoclopramide 0.15 mg/kg i.v. vs. placebo (2 studies) [RB 2.28, 95% CI 1.37–3.78] - metoclopramide 0.15 mg/kg oral vs. placebo (1 study) [RB 0.86, 95% CI 0.50–1.48] PON up to 48 hours: - metoclopramide 0.25 mg/kg i.v. vs. placebo (1 study) [RB 1.37, 95% CI 0.92–2.04] PONV up to 48 hours: - metoclopramide 0.10 mg/kg i.v. vs. placebo (1 study) [RB 1.08, 95% CI 0.65–1.80] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RB, relative benefit; RR, relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence indicates that metoclopramide is more effective than placebo (using 0.15 mg/kg or 0.25 mg/kg doses) in reducing early postoperative vomiting (up to 6 hours). Metoclopramide appears to be inferior to ondansetron in reducing vomiting. There also appears to be a trend towards metoclopramide being less effective than droperidol.

Table 5: Results of systematic reviews assessing the effectiveness of prophylactic perphenazine in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - perphenazine vs. placebo (1 study) [OR 0.50, 95% CI 0.31–0.82] Henzi (2000) [RB < 1 indicates a positive treatment effect] POV up to 6 hours: - dexamethasone 150 mcg/kg i.v. vs. perphenazine 70 mcg/kg i.v. (1 study) [RB 0.74, 95% CI 0.63-0.86] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RB, relative benefit. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that perphenazine may be more effective than placebo in reducing postoperative nausea and/or vomiting. Perphenazine may also be more effective than dexamethasone (at the doses recommended in the current guidelines).

7 WHO EML – Anti-emetics – January 2009

Table 6: Results of systematic reviews assessing the effectiveness of prophylactic droperidol in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - droperidol vs. placebo (1 study) [OR 0.99, 95% CI 0.44–2.22] Engelman (2008) [RR < 1 indicates a positive treatment effect] Any PONV - droperidol (5-25 mcg/kg) vs. placebo (3 studies) [RR 0.62, 95% CI 0.52-0.74] - ondansetron (0.15 mg/kg) + droperidol (0.15/25 mcg/kg) vs. placebo (1 study) [RR 0.22, 95% CI 0.10-0.45] Lim (1999) [RR < 1 indicates a positive treatment effect] POV up to 24h: - ondansetron vs. droperidol (9 studies) [RR 0.67, 95% CI 0.49–0.90] PONV up to 24h: - ondansetron vs. droperidol (13 studies) [RR 0.70, 95% CI 0.53–0.92] Tramer (1995) [OR > 1 indicates a positive treatment effect] (strabismus surgery) POV up to 6 hours: - droperidol 10 mcg/kg vs. placebo (1 study) [OR 1.6, 95% CI 0.4–7.2] - droperidol 20 mcg/kg vs. placebo (1 study) [OR 1.9, 95% CI 0.7–5] - droperidol 50 mcg/kg vs. placebo (2 studies) [OR 1.5, 95% CI 0.7–3.2] - droperidol 75 mcg/kg vs. placebo (10 studies) [OR 3.3, 95% CI 2.4–4.7] POV up to 48 hours: - droperidol 50 mcg/kg vs. placebo (2 studies) [OR 1.3, 95% CI 0.5–3.4] - droperidol 75 mcg/kg vs. placebo (10 studies) [OR 2.5, 95% CI 1.7–3.6] Domino (1999) [OR < 1 indicates a positive treatment effect] Any POV: - ondansetron vs droperidol (9 studies) [OR 0.49, 95% CI 0.30–0.80] - droperidol vs metoclopramide (7 studies) [OR 0.63, 95% CI 0.36–1.10] Henzi (2000b) [RR > 1 indicates a positive treatment effect] POV up to 6 hours: - droperidol 10–20 mcg/kg i.v. vs. placebo (3 studies) [RR 1.17, 95% CI 1.06–1.29] - droperidol 40–50 mcg/kg i.v. vs. placebo (3 studies) [RR 1.34, 95% CI 1.09–1.64] - droperidol 75 mcg/kg i.v. vs. placebo (11 studies) [RR 1.47, 95% CI 1.20–1.82] - droperidol 50 mcg/kg i.m. vs. placebo (1 study) [RR 1.16, 95% CI 1.01–1.34] - droperidol 200 mcg/kg i.m. vs. placebo (1 study) [RR 1.18, 95% CI 1.05–1.32] - droperidol 200 mcg/kg oral vs. placebo (1 study) [RR 1.44, 95% CI 1.13–1.85] POV up to 24 hours: - droperidol 5–20 mcg/kg i.v. vs. placebo (2 studies) [RR 1.22, 95% CI 1.07–1.39] - droperidol 50 mcg/kg i.v. vs. placebo (2 studies) [RR 1.51, 95% CI 1.09–2.11] - droperidol 75 mcg/kg i.v. vs. placebo (10 studies) [RR 1.55, 95% CI 1.17–2.06] - droperidol 300 mcg/kg oral vs. placebo (1 study) [RR 1.66, 95% CI 1.09–2.53] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RR, relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence indicates that droperidol is more effective than placebo in reducing postoperative nausea and/or vomiting. Most of the studies of droperidol used doses in excess of those recommended in current guidelines (10–15 mcg/kg); and there is only a limited body of evidence to support the use of lower doses. The combination of droperidol and ondansetron appears to be effective while droperidol alone appears to be inferior to ondansetron alone in reducing nausea and vomiting. There is also a trend towards a lower incidence of vomiting with droperidol compared to metoclopramide.

8 WHO EML – Anti-emetics – January 2009

Table 7: Results of systematic reviews assessing the effectiveness of prophylactic dixyrazine in children Results Tramer (1995) [OR > 1 indicates a positive treatment effect] (strabismus surgery) POV up to 6 hours: - dixyrazine 0.25 mg/kg vs. placebo (2 studies) [OR 5.6, 95% CI 1.5–20] POV up to 48 hours: - dixyrazine 0.25 mg/kg vs. placebo (2 studies) [OR 5.4, 95% CI 2.8–10.2] Abbreviations: CI, confidence interval; OR, odds ratio; POV, postoperative vomiting. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that dixyrazine may be more effective than placebo in reducing postoperative nausea and/or vomiting.

Serotonin 5-HT3 antagonists

Table 8: Results of systematic reviews assessing the effectiveness of prophylactic ondansetron in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - ondansetron vs. placebo (10 studies) [OR 0.36, 95% CI 0.29–0.46] Engelman (2008) [RR < 1 indicates a positive treatment effect] Any PONV: - ondansetron (0.1–0.15 mg/kg) vs. placebo (14 studies) [RR 0.54, 95% CI 0.51–0.56] - ondansetron (0.05-0.15 mg/kg) plus dexamethasone (0.1-1 mg/kg) vs. ondansetron or dexamethasone alone (5 studies) [RR 0.33, 95% CI 0.27-0.40] - ondansetron (0.15 mg/kg) + droperidol (0.15/25 mcg/kg) vs. placebo (1 study) [RR 0.22, 95% CI 0.10-0.45] - ondansetron (0.15 mg/kg) + dexamethasone (0.2 mg/kg) vs. placebo (1 study) [RR 0.22, 95% CI 0.07-0.61] - ondansetron + dexamethasone vs. placebo (indirect comparison) [RR 0.17, 95% CI 0.14-0.21] Lim (1999) [RR < 1 indicates a positive treatment effect] POV up to 24 hours: - ondansetron vs. droperidol (9 studies) [RR 0.67, 95% CI 0.49–0.90] - ondansetron vs. metoclopramide (8 studies) [RR 0.56, 95% CI 0.44–0.71] PONV up to 24 hours: - ondansetron vs. droperidol (13 studies) [RR 0.70, 95% CI 0.53–0.92] Tramer (1995) [OR > 1 indicates a positive treatment effect] (strabismus surgery) POV up to 6 hours: - ondansetron 0.15 mg/kg vs. placebo (1 study) [OR 6.5, 95% CI 2.2–19.5] POV up to 48 hours: - ondansetron 0.15 mg/kg vs. placebo (1 study) [OR 4.2, 95% CI 1.6–11.6]

9 WHO EML – Anti-emetics – January 2009

Results Domino (1999) [OR < 1 indicates a positive treatment effect] Any POV: - ondansetron vs metoclopramide (6 studies) [OR 0.33, 95% CI 0.27–0.39] - ondansetron vs droperidol (9 studies) [OR 0.49, 95% CI 0.30–0.80] Figueredo (1998) [OR > 1 indicates a positive treatment effect] POV up to 8 hours: - ondansetron 0.10 mg/kg vs. placebo (3 studies) [OR 4.54, 95% CI 2.68–7.71] - ondansetron 0.15 mg/kg vs. placebo (5 studies) [OR 5.14, 95% CI 3.23–8.17] POV up to 24 hours: - ondansetron 0.05 mg/kg vs. placebo (2 studies) [OR 2.36, 95% CI 0.49–11.39] - ondansetron 0.10 mg/kg vs. placebo (5 studies) [OR 2.87, 95% CI 1.63–5.04] - ondansetron 0.15 mg/kg vs. placebo (5 studies) [OR 3.02, 95% CI 1.99–4.59] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RR, relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence indicates that ondansetron is more effective than placebo in reducing postoperative nausea and/or vomiting. The combination of ondansetron with dexamethasone appears to more effective than either therapy alone. The combination of ondansetron with droperidol also appears effective. Ondansetron appears to be superior to both metoclopramide and droperidol in reducing nausea and vomiting.

Table 9: Results of systematic reviews assessing the effectiveness of prophylactic granisetron in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - granisetron vs. placebo (3 studies) [OR 0.11, 95% CI 0.06–0.19] Engelman (2008) [RR < 1 indicates a positive treatment effect] Any PONV: - granisetron (0.04 mg/kg) vs. placebo (3 studies) [RR 0.31, 95% CI 0.20-0.45] - granisetron (0.04 mg/kg) + dexamethasone (0.15 mg/kg) vs. placebo (1 study) [RR 0.10, 95% CI 0.02-0.47] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RR, relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that granisetron may be more effective than placebo in reducing postoperative nausea and/or vomiting. The combination of granisetron with dexamethasone also appears effective.

Table 10: Results of systematic reviews assessing the effectiveness of prophylactic dolasetron in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - dolasetron vs. placebo (1 study) [OR 0.25, 95% CI 0.1–0.59]

10 WHO EML – Anti-emetics – January 2009

Results Engelman (2008) [RR < 1 indicates a positive treatment effect] Any PONV: - dolasetron (0.35 mg/kg i.v. or 1.8 mg/kg oral) vs. placebo (2 studies) [RR 0.39, 95% CI 0.25- 0.56] - dolasetron (0.5 mg/kg) + dexamethasone (1.0 mg/kg) vs. dexamethasone (1 study) [RR 0.48, 95% CI 0.25-0.82] - dolasetron + dexamethasone vs. placebo (indirect comparison) [RR 0.21, 95% CI 0.12-0.39] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RR, relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that dolasetron may be more effective than placebo in reducing postoperative nausea and/or vomiting. The combination of dolasetron with dexamethasone also appears effective compared to placebo or dexamethasone alone.

Table 11: Results of systematic reviews assessing the effectiveness of prophylactic tropisetron in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - tropisetron vs. placebo (2 studies) [OR 0.15, 95% CI 0.06–0.35] Engelman (2008) [RR < 1 indicates a positive treatment effect] Any PONV: - tropisetron (0.1-0.2 mg/kg) vs. placebo (5 studies) [RR 0.41, 95% CI 0.34-0.50] - tropisetron (0.1 mg/kg) + dexamethasone (0.15 or 0.50 mg/kg) vs. tropisetron (2 studies) [RR 0.49, 95% 0.34-0.67] - tropisetron + dexamethasone vs. placebo (indirect comparison) [RR 0.20, 95% CI 0.14-0.30] Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RR, relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that tropisetron may be more effective than placebo in reducing postoperative nausea and/or vomiting. The combination of tropisetron with dexamethasone also appears effective compared to placebo or tropisetron alone.

Steroids

Table 12: Results of systematic reviews assessing the effectiveness of prophylactic dexamethasone in children Results Bolton (2006) [OR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - dexamethasone vs. placebo (9 studies) [RR 0.48, 95% CI 0.40–0.57] Engelman (2008) [RR < 1 indicates a positive treatment effect] Any PONV: - dexamethasone (0.050-1.0 mg/kg) vs. placebo (13 studies) [RR 0.53 95% CI 0.49-0.56] - ondansetron (0.05-0.15 mg/kg) + dexamethasone (0.1-1 mg/kg) vs. ondansetron or dexamethasone alone (5 studies) [RR 0.33, 95% CI 0.27-0.40] - tropisetron (0.1 mg/kg) + dexamethasone (0.15 or 0.50 mg/kg) vs. tropisetron (2 studies) [RR 0.49, 95% 0.34-0.67]

11 WHO EML – Anti-emetics – January 2009

Results - dolasetron (0.5 mg/kg) + dexamethasone (1.0 mg/kg) vs. dexamethasone (1 study) [RR 0.48, 95% CI 0.25-0.82] - ondansetron (0.15 mg/kg) + dexamethasone (0.2 mg/kg) vs. placebo (1 study) [RR 0.22, 95% CI 0.07-0.61] - granisetron (0.04 mg/kg) + dexamethasone (0.15 mg/kg) vs. placebo (1 study) [RR 0.10, 95% CI 0.02-0.47] - ondansetron + dexamethasone vs. placebo (indirect comparison) [RR 0.17, 95% CI 0.14-0.21] - tropisetron + dexamethasone vs. placebo (indirect comparison) [RR 0.20, 95% CI 0.14-0.30] - dolasetron + dexamethasone vs. placebo (indirect comparison) [RR 0.21, 95% CI 0.12-0.39] Goldman (2000) [RR < 1 indicates a positive treatment effect] (tonsillectomy surgery) Any POV: - dexamethasone vs. placebo (5 studies) [RD 0.73, 95% CI 0.58–0.88] Steward (2001) [RR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - dexamethasone vs. placebo (7 studies) [RR 0.55, 95% CI 0.41–0.74] Steward (2003) [RR < 1 indicates a positive treatment effect] (tonsillectomy surgery) POV up to 24 hours: - dexamethasone vs. placebo (8 studies) [RR 0.54, 95% CI 0.42–0.69] Henzi (2000) [RB > 1 indicates a positive treatment effect] POV up to 6 hours: - dexamethasone 1–1.5 mg/kg i.v. vs. placebo (3 studies) [RB 1.17, 95% CI 1.02–1.34] - dexamethasone 150 mcg/kg i.v. vs. perphenazine 70 mcg/kg i.v. (1 study) [RB 0.74, 95% CI 0.63-0.86] POV up to 24 hours: - dexamethasone 0.5 mg/kg i.v. vs. placebo (1 study) [RB 1.03, 95% CI 0.91–1.18] - dexamethasone 1–1.5 mg/kg i.v. vs. placebo (3 studies) [RB 1.80, 95% CI 1.47–2.21] - dexamethasone 4 mg + granisetron 40 mcg/kg i.v. vs. granisetron 40 mcg/kg i.v. (1 study) [RB 1.27, 95% CI 1.01–1.61] Warren (2008) - 4 studies in children reported control group incidences of overall postoperative vomiting of between 51% and 88%. Overall, following administration of dexamethasone the incidence of vomiting was reduced to a range from 20%–48% Abbreviations: CI, confidence interval; OR, odds ratio; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RB, relative benefit; relative risk. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence indicates that dexamethasone is more effective than placebo in reducing postoperative nausea and/or vomiting. The combination of dexamethasone with any of the serotonin 5-HT3 antagonists (ondansetron, granisetron, dolasetron, tropisetron) appears effective.

12 WHO EML – Anti-emetics – January 2009

Anti-cholinergics

Table 13: Results of systematic reviews assessing the effectiveness of prophylactic hyoscine in children Results Tramer (1995) [OR > 1 indicates a positive treatment effect] (strabismus surgery) POV up to 48 hours: - hyoscine 0.375-0.75 mg transdermal patch vs. placebo (1 study) [OR 4.2, 95% CI 1.3–13.7] Abbreviations: CI, confidence interval; OR, odds ratio; POV, postoperative vomiting. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that hyoscine (transdermal patch) may be more effective than placebo in reducing postoperative nausea and/or vomiting.

Table 14: Results of systematic reviews assessing the effectiveness of prophylactic atropine in children Results Tramer (1995) [OR > 1 indicates a positive treatment effect] (strabismus surgery) POV up to 6 hours: - atropine 10 mcg/kg vs. placebo (1 study) [OR 1.3, 95% CI 0.3–4.7] POV up to 48 hours: - atropine 10 mcg/kg vs. placebo (1 study) [OR 0.4, 95% CI 0.1–0.2] Abbreviations: CI, confidence interval; OR, odds ratio; POV, postoperative vomiting. Note: Systematic reviews that did not present a separate analysis of children studies were not included in the overview.

Summary: The body of evidence suggests that atropine is no more effective than placebo in reducing postoperative nausea and/or vomiting.

Efficacy discussion

The current evidence suggests that dimenhydrinate, metoclopramide, perphenazine, droperidol, dixyrazine, ondansetron, granisetron, dolasetron, tropisetron, dexamethasone and hyoscine (transdermal patch) are effective for the prevention of post-operative nausea and vomiting in children. Metoclopramide, droperidol, ondansetron and dexamethasone are the most well-studied treatments. The available evidence does not support the use of atropine. No systematic reviews evaluated the efficacy of promethazine (anti-histamine, currently on WHO essential medicines list) in the management of postoperative nausea and vomiting in children.

Based on comparative efficacy studies it appears that ondansetron is superior to both metoclopramide and droperidol in reducing postoperative vomiting. The combination of dexamethasone with ondansetron (or any serotonin 5HT3 antagonist) appears to be superior to either treatment alone.

Reviews analysing studies in both adults and children (but not presenting a separate analysis of children studies) were broadly consistent with the current review (Carlisle & Stevenson 2006, Eberhardt et al 2000, Habib et al 2004, Kranke et al 2002b, Tramer et al

13 WHO EML – Anti-emetics – January 2009

1997b). These mixed population reviews further support the use of metoclopramide, droperidol, ondansetron, granisetron, dolasetron, tropisetron and hyoscine (transdermal patch) as anti-emetic treatments. Additionally cyclizine was also identified as an effective prophylactic therapy (Carlisle & Stevenson 2006).

It should be noted that current treatment guidelines do not recommend the use metoclopramide, dixyrazine or hyoscine (transdermal patch) for the prevention of postoperative nausea and vomiting in children (Gan et al 2007). The guidelines specifically do not recommend metoclopramide at standard clinical doses based on the review by Henzi et al (1999), however the current review indicates that metoclopramide at doses of 0.15 mg/kg and 0.25 mg/kg may be an effective treatment to prevent early postoperative vomiting. The guidelines make no specific comment in regards to the use of dixyrazine or hyoscine (transdermal patch) in children.

Finally, two reviews were also identified that assessed the efficacy of treatments for established postoperative nausea and vomiting. These reviews concluded that serotonin 5HT3 antagonists are effective treatments compared to placebo (Kazemi et al 2001) and that there is no evidence to suggest that ondansetron is better than other available therapies (metoclopramide and droperidol) (Tramer et al 1997).

7.2 Summary of available safety data

The product information available for treatments identified as effective (see Section 7.1) were reviewed to identify any relevant safety issues. A summary of the key safety information is presented in Table 15.

The safety of most of these treatments has not been adequately established in children less than 2 years of age (the most notable exception is ondansetron which is approved by the FDA for children greater than 1 month of age).

Three treatments have specific safety issues that need to be highlighted: o The US product information for droperidol contains an FDA ‘black box warning” regarding the risk of cardiotoxicity. Treatment guidelines recommend that droperidol only be used if other therapies have failed and the patient is being admitted to hospital (Gan et al 2007). o The Australian product information for dolasetron includes a contraindication by the TGA for the use of dolasetron in children less than 18 years of age. This appears to be due to cardiotoxicity concerns in children. o The Australian product information for metoclopramide warns that children are more likely to experience adverse events than adults (including extrapyramidal side effects). The product information indicates that metoclopramide should be restricted to the following conditions when used to treat children and young adults under 20 years of age: severe intractable vomiting of known cause; vomiting associated with radiation therapy or intolerance to cytotoxic drugs; assist in small bowel intubation.

14 WHO EML – Anti-emetics – January 2009

Table 15: Key safety information Drugs Key safety information and adverse reactions Dimenhydrinate • Adverse reactions: Drowsiness especially on high dosage; dizziness, headache, blurred vision, tinnitus, incoordination, palpitations, hypotension, dry mouth, lassitude, excitement, nausea & fixed drug eruption. Metoclopramide • Adverse reactions: Most frequent - restlessness, drowsiness, fatigue, lassitude. Less frequent - insomnia, headache, dizziness, nausea, or bowel disturbances. Rare – acute depression. Very rare - abnormalities of cardiac conduction, neuroleptic malignant syndrome; extrapyramidal reactions (usually dystonic, uncommon at normal dosage); tardive dyskinesia (elderly, long-term use); methaemoglobinaemia. Serious adverse reactions: neuroleptic malignant syndrome (potentially fatal, very rare). Should not be given to children unless a clear indication has been established for its use, because of the higher incidence of adverse reactions in this age group. Perphenazine • Adverse reactions: CNS effects (e.g. extrapyramidal reactions, tardive dyskinesia, cerebral oedema, convulsive seizures, neuroleptic malignant syndrome, adverse behavioural effects, drowsiness); autonomic effects (e.g. dry mouth, nausea, vomiting, constipation, blurred vision); allergic effects (e.g. eczema, erythema, dermatitis, fever, asthma); endocrine effects; cardiovascular effects (postural hypotension, tachycardia, brachycardia); agranulocytosis. Serious adverse reactions: neuroleptic malignant syndrome (potentially fatal); adynamic ileus (occasional, can be fatal if severe especially in psychiatric patients); sudden death. Droperidol • Black box warning (FDA): Potential for serious proarrhythmic effects and death. Contraindicated in patients with known or suspected QT prolongation, including patients with congenital long QT syndrome; not recommended for any use other than for the treatment of perioperative nausea and vomiting in patients for whom other treatments are ineffective or inappropriate. • Adverse reactions: Most common - drowsiness, mild to moderate hypotension. Uncommon - dizziness, chills and/or shivering, restlessness, isolated cases of anxiety & postoperative hallucinatory episodes, tachycardia; extrapyramidal reactions (low incidence); tardive dyskinesia; respiratory depression, apnoea & muscular rigidity when used with a narcotic analgesic (respiratory arrest if untreated). Rare - QT interval prolongation, ventricular arrhythmias, body temperature dysregulation. Serious adverse reactions - neuroleptic malignant syndrome (potentially fatal), QT prolongation & serious arrhythmias; sudden death. Dixyrazine • Adverse reactions: Tachycardia, transient hypotension, allergic reactions (erythema, pruritus, eczema, local edema, photosensitivity, exfoliative dermatitis, severe burning sensation), hair loss, hair depigmentation, ichthyosis, agranulocytosis, thrombocytopenia, hepatic impairment, extrapyramidal reactions (including tardive dyskinesia), fatigue, drowsiness, restlessness, parkinsonian symptoms, akathisia, neuroleptic malignant syndrome, blurred vision, blepharocunjunctivitis, urinary and ejaculatory disturbances, asthmatic crisis. Ondansetron • Adverse reactions: Very common – headache. Common – constipation, xerostomia, warm sensation, flushing, injection site reactions. Uncommon – CNS disorders (seizures, movement disorders), cardiac disorders (arrhythmia, chest pain, bradycardia); hiccups; hypotension. Rare - immediate hypersensitivity reactions, sometimes severe, including anaphylaxis. Very rare - transient blindness (during IV administration).

15 WHO EML – Anti-emetics – January 2009

Drugs Key safety information and adverse reactions Granisetron • Adverse reactions: Most common - headache, constipation. Common – fever, hypertension, transient increases in AST & ALT, agitation, anxiety, CNS stimulation, dizziness, insomnia, somnolence, skin rashes, taste disorders. Rare - hypotension, arrhythmias, sinus bradycardia, atrial fibrillation, varying degrees of atrioventricular block, ventricular ectopy including nonsustained tachycardia, ECG abnormalities, angina pectoris, syncope, hypersensitivity reactions (e.g. anaphylaxis, shortness of breath, hypotension, urticaria), extrapyramidal syndrome. Dolasetron • Contraindication (TGA): Children less than or equal to 18 years • Adverse reactions: Very common – headache. Common - bradycardia, diarrhoea, dizziness, hypotension, increased serum transaminases, tachycardia. Uncommon - abdominal pain, chest pain, constipation, dyspepsia, fatigue, hypertension, orthostatic hypotension. Rare - intestinal obstruction, pancreatitis, jaundice, seizure, bronchospasm, myocardial ischaemia, syncope, severe bradycardia, oedema, anaphylactic/ anaphylactoid reactions including skin reactions such as rash, pruritus and urticaria, respiratory reactions such as bronchospasm. Very rare - severe hypotension, bradycardia, possibly loss of consciousness (IV), wide complex tachycardia or ventricular tachycardia & ventricular fibrillation/cardiac arrest (IV), facial oedema/angioedema, shock. Tropisetron • Adverse reactions: Most common - headache (2 mg dose), constipation (5 mg dose). Less common – fatigue, dizziness, somnolence, GI upset, anorexia, hypersensitivity, chest discomfort, prolonged QT interval, syncope, generalised urticaria. Rare - rash, erythema, anaphylactic reactions/shock. Very rare – collapse, CV arrest. Dexamethasone • Adverse reactions: Mainly result from withdrawal or from prolonged use of high doses. More common – salt & water retention, hypertension, arrhythmias & cardiac arrest, behavioural & personality changes (large doses), impaired wound healing, facial plethora, acne form eruption on the face, chest & back, corticosteroid induced purpura, endocrine effects involving the hypothalamic-pituitary-adrenal axis, the genitals, the parathyroid & thyroid, metabolic effects involving the carbohydrates, suppression of growth (children), Cushing's syndrome, disorders of menstruation, antagonism between the parathyroids & hypercorticism, increased gluconeogenesis, decreased glucose tolerance & sensitivity to insulin, steroid diabetes (high dose), growth retardation (long-term use), increased frequency & severity of infections, osteoporosis & vertebral compression fractures (all ages), myopathy (occasional, large dose), avascular aseptic necrosis of bone; posterior subcapsular cataract (10% incidence if used long-term). Less common – pancreatitis, peptic ulceration, manifestation of latent epilepsy, benign intracranial hypertension (long-term use), increased intraocular pressure, glaucoma, blindness. Severe or life-threatening reactions - suppression of the hypothalamic-pituitary-adrenal axis (repeated use of glucocorticoids); withdrawal syndrome after termination of treatment; in some cases, acute adrenal insufficiency after a period of glucocorticoid treatment has proved fatal. Hyoscine • Adverse reactions: Cardiovascular system: bradycardia (at low doses), initial tachycardia followed by bradycardia (at higher doses), hypotension, arrhythmia. Central nervous system: sedation, drowsiness, irritability, disorientation, hallucinations, impairment of memory and concentration, dizziness, confusion, tremor, acute toxic psychosis, restlessness, delirium, excitement. Symptoms of CNS depression predominate at

16 WHO EML – Anti-emetics – January 2009

Drugs Key safety information and adverse reactions therapeutic doses. Symptoms of CNS stimulation predominate at higher doses, and at therapeutic doses in the presence of pain. Gastrointestinal: dry mouth, constipation, nausea, vomiting. Genitourinary system: Difficulty in urinating. Ocular: blurred vision, mydriasis, closed angle glaucoma. Skin and appendages: rashes, erythema, redness or irritation at injection site. Care should be taken in titrating the dose of hyoscine in children as they are more likely than adults to experience adverse events. Abbreviations: Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; CV, cardiovascular; ECG, electrocardiographic; FDA, Food and Drug Administration (US); GI, gastrointestinal; IV, intravenous; TGA, Therapeutic Goods Administration (Australia) Source: DRUGDEX® evaluations (www.micromedex.com); MARTINDALE® database (www.micromedex.com); MIMS® Australia (http://www.mims.com.au);

7.3 Summary of available cost data

An estimated price per dose was calculated to facilitate simple comparisons of costs between treatments identified as effective (see Section 7.1). A summary of indicative prices is presented in Table 16. The dosing information was based on current treatment guidelines (Gan et al 2007) supplemented with additional information when necessary (see Appendix C). The price per dose was calculated for three representative weights as the dose of most treatments is weight-dependent. Details of available pricing data are presented in Appendix C.

There is a notable difference in the cost of the serotonin 5HT3 antagonists compared to the other therapies. However, it should be noted that both ondansetron and granisetron are currently (or soon will be, depending on patent status in each country) available as generics which may further affect the price of these medications.

Table 16: Price per dose for children of representative weights Drug Cost Dose and price per dosea ($US/mg) 10kg child 20kg child 40kg child Maximal dose Single agents 5mg 10mg 20mg 25mg Dimenhydrinate $0.003/mg $0.01 $0.03 $0.05 $0.06 1.0-5.0mg 2.0-10.0mg 4.0-20.0mg Metoclopramide $0.01/mg NR $0.01-$0.06 $0.02-$0.12 $0.05-$0.25 Perphenazine Indicative price could not be determined 0.1-0.15mg 0.2-0.3mg 0.4-0.6mg 1.25mg Droperidol $0.17/mg $0.02-$0.03 $0.03-$0.05 $0.07-$0.10 $0.22 Dixyrazine Indicative price could not be determined 0.5-1.0mg 1.0-2.0mg 2.0-4.0mg 4mg Ondansetron $1.01/mg $0.50-$1.01 $1.01-$2.02 $2.02-$4.04 $4.04

17 WHO EML – Anti-emetics – January 2009

Drug Cost Dose and price per dosea ($US/mg) 10kg child 20kg child 40kg child Maximal dose 0.4mg 0.6mg 0.6mg 0.6mg Granisetron $2.94/mg $1.18 $1.76 $1.76 $1.76 Dolasetron Indicative price could not be determined 1mg 2mg 2mg 2mg Tropisetron $2.69/mg $2.69 $5.36 $5.36 $5.36 1.5mg 3.0mg 3-5.0mg 5.0mg Dexamethasoneb $0.02/mg $0.03 $0.06 $0.10 $0.10 Hyoscine Indicative price could not be determined (transdermal) Combinations Ondansetron/dexamethasone 0.5/1.5mg 1.0/3.0mg 2.0/5.0mg 4.0/5.0mg Total cost $0.53 $1.07 $2.12 $4.14 Abbreviations: NR, not reported. a Because the dose varies with weight, data for three representative weights are provided, 10kg, 20kg, and 40mg. The 50th percentiles for 2-year olds are 12.2kg and 11.5 for boys and girls, respectively, and for 5-year olds they are 18.3kg and 18.2kg, respectively, (www.who.int/childgrowth/standards). For some drugs the doses in heavier children are limited by the daily maximal dose. Wastage is not included in the calculations. b The less expensive dexamethasone injection formulation, 5mg/mL, on a per mg basis was used (See Appendix C)

8. International regulatory status

The regulatory status of treatments identified as effective (see Section 7.1) were reviewed to identify any relevant issues (in Australia and the US). A summary of the key regulatory information is presented in Appendix D.

Dimenhydrinate, metoclopramide, perphenazine, droperidol, ondansetron and dolasetron have regulatory approval specifically for the management of postoperative nausea and vomiting in children (or have a broader indication that also includes this patient group). It should be noted that while dolasetron is approved in the US for children it has been specifically contraindicated for use in this patient group in Australia. It should also be mentioned that the approval of perphenazine relates to children at least 12 years of age.

Many of the treatments have also been approved for related indications in children such as motion sickness and chemotherapy-induced nausea and vomiting. The majority of the treatments are approved for the management of postoperative nausea and vomiting in adults.

9. General discussion

The clinical evidence suggests that dimenhydrinate, metoclopramide, perphenazine, droperidol, dixyrazine, ondansetron, granisetron, dolasetron, tropisetron, dexamethasone and hyoscine (transdermal patch) may be effective for the prevention of post-operative nausea and vomiting in children. There was no evidence located to support the efficacy of promethazine (currently listed on the WHO Model List of Essential Medicines as an anti- emetic medication for children).

18 WHO EML – Anti-emetics – January 2009

While perphenazine, dixyrazine and hyoscine (transdermal patch) appear effective, the evidence base supporting these treatments is more limited than for other treatments evaluated. Dixyrazine and hyoscine (transdermal patch) are not currently approved for the management of postoperative nausea and vomiting in children and perphenazine is only approved for use in children at least 12 years of age.

Dimenhydrinate appears to be an effective prophylaxis for nausea and vomiting for children. Dimenhydrinate is approved for the management of nausea and vomiting in children.

Metoclopramide (currently listed on the WHO Model List of Essential Medicines as an anti-emetic medication for children) and droperidol appear to be effective in reducing postoperative nausea and vomiting in children. Metoclopramide and droperidol are both approved for the management of postoperative nausea and vomiting in children. However there are safety concerns regarding each of these treatments. Because of the FDA ‘black box warning” regarding the risk of cardiotoxicity with droperidol, current guidelines recommend that droperidol only be used in children if other therapies have failed and the patient is being admitted to hospital. Additionally the Australian product information for metoclopramide warns of the increased incidence of adverse events in children (including extrapyramidal side effects) and recommends that treatment should be restricted to children with severe intractable vomiting of known cause; vomiting associated with radiation therapy or intolerance to cytotoxic drugs; and to assist in small bowel intubation.

Ondansetron, granisetron, dolasetron and tropisetron appear to be effective in reducing postoperative nausea and vomiting in children. Only ondansetron and dolasetron are approved for the management of postoperative nausea and vomiting in children. Safety concerns with dolasetron (risk of cardiotoxicity in children) mean that assumptions of a class effect with the serotonin 5HT3 antagonists (i.e. comparable safety and efficacy) may not be appropriate. There is a substantial body of evidence supporting the use of ondansetron in children. The evidence supporting granisetron and tropisetron appears more limited however these treatments might be considered suitable alternatives to ondansetron in some settings.

There is a substantial body of evidence to indicate that dexamethasone is an effective therapy for postoperative nausea and vomiting in children either as a single agent or combined with a serotonin 5HT3 antagonist (the combination of a serotonin 5HT3 antagonist with dexamethasone appears to more effective than either therapy alone). Dexamethasone is not currently approved specifically for the management of postoperative nausea and vomiting in children.

19 WHO EML – Anti-emetics – January 2009

Reference List o Bolton CM, Myles PS, Nolan T, Sterne JA (2006), Prophylaxis of postoperative vomiting in children undergoing tonsillectomy: A systematic review and meta- analysis, British Journal of Anaesthesia 97: 593-604 o Carlisle JB, Stevenson CA (2006), Drugs for preventing postoperative nausea and vomiting, Cochrane database of systematic reviews (Online): CD004125 o Domino KB, Anderson EA, Polissar NL, Posner KL (1999), Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: A meta- analysis, Anesthesia and analgesia 88: 1370-1379 o Eberhart LH, Morin AM, Bothner U, Georgieff M (2000), Droperidol and 5-HT3- receptor antagonists, alone or in combination, for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomised controlled trials, Acta Anaesthesiologica Scandinavica 44: 1252-1257 o Engelman E, Salengros JC, Barvais L (2008), How much does pharmacologic prophylaxis reduce postoperative vomiting in children? Calculation of prophylaxis effectiveness and expected incidence of vomiting under treatment using Bayesian meta-analysis, Anesthesiology 109: 1023-1035 o Figueredo ED, Canosa LG (1998), Ondansetron in the prophylaxis of postoperative vomiting: A meta- analysis, Journal of Clinical Anesthesia 10: 211-221 o Gan TJ, Meyer TA, Apfel CC, Chung F, Davis PJ, Habib AS, Hooper VD, Kovac AL, Kranke P, Myles P, Philip BK, Samsa G, Sessler DI, Temo J, Tramer MR, Kolk CV, Watcha M (2007), Society for Ambulatory Anesthesia Guidelines for the Management of Postoperative Nausea and Vomiting, Ambulatory Anesthesiology 105: 1615-1628 o Goldman AC, Govindaraj S, Rosenfeld RM (2000), A meta-analysis of dexamethasone use with tonsillectomy, Otolaryngology - Head and Neck Surgery 123: 682-686 o Habib AS, El-Moalem HE, Gan TJ (2004), The efficacy of the 5-HT3 receptor antagonists combined with droperidol for PONV prophylaxis is similar to their combination with dexamethasone. A meta-analysis of randomized controlled trials, Canadian journal of anaesthesia 51: 311-319 o Henzi I, Walder B, Tramer MR (1999), Metoclopramide in the prevention of postoperative nausea and vomiting: A quantitative systematic review of randomized, placebo-controlled studies, British Journal of Anaesthesia 83: 761-771 o Henzi I, Sonderegger T, Tramer MR (2000), Efficacy, dose-response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting, Canadian Journal of Anaesthesia 47: 537-551 o Henzi I, Walder B, Tramer MR (2000b), Dexamethasone for the prevention of postoperative nausea and vomiting: A quantitative systematic review, Anesthesia and analgesia 90: 186-194

20 WHO EML – Anti-emetics – January 2009 o Kazemi-Kjellberg F, Henzi I, Tramer MR (2001), Treatment of established postoperative nausea and vomiting: a quantitative systematic review, BMC Anesthesiology 1: 2 o Kovac AL (2007), Management of Postoperative Nausea and Vomiting in Children, Pediatric Drugs 9: 47-69 o Kranke P, Apfel CC, Eberhart LH, Georgieff M, Roewer N (2001), The influence of a dominating centre on a quantitative systematic review of granisetron for preventing postoperative nausea and vomiting, Acta Anaesthesiologica Scandinavica 45: 659-670 o Kranke P, Morin AM, Roewer N, Eberhart LHJ (2002), Dimenhydrinate for prophylaxis of postoperative nausea and vomiting: A meta-analysis of randomized controlled trials, Acta Anaesthesiologica Scandinavica 46: 238-244 o Kranke P, Morin AM, Roewer N, Wulf H, Eberhart LH (2002b), The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: A quantitative systematic review, Anesthesia and analgesia 95: 133-143 o Leslie JB, Gan TJ (2006), Meta-analysis of the safety of 5-HT3 antagonists with dexamethasone or droperidol for prevention of PONV, Annals of Pharmacotherapy 40: 856-872 o Lim LLY, Dear KBG, Heller RF (1999), A systematic review of the antiemetic efficacy of prophylactic ondansetron compared with droperidol and with metoclopramide in children, Clinical Research and Regulatory Affairs 16: 59-70 o McQuay HJ, Moore RA (1998), Postoperative analgesia and vomiting, with special reference to day- case surgery: A systematic review, Health Technology Assessment 2: ii-230 o Rose JB, Watcha MF (1999), Postoperative nausea and vomiting in paediatric patients, British Journal of Anaesthesia 83: 104-117 o Steward DL, Welge JA, Myer CM (2001), Do steroids reduce morbidity of tonsillectomy? Meta-analysis of randomized trials, Laryngoscope 111: 1712-1718 o Steward DL, Welge JA, Myer CM (2003), Steroids for improving recovery following tonsillectomy in children, Cochrane database of systematic reviews (Online): CD003997 o Tramer M, Moore A, McQuay H (1995), Prevention of vomiting after paediatric strabismus surgery: a systematic review using the numbers-needed-to-treat method (Structured abstract), British Journal of Anaesthesia 75: 556-561 o Tramer MR, Moore RA, Reynolds DJM, McQuay HJ (1997), A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting, British Medical Journal 314: 1088-1092 o Tramer MR, Reynolds DJM, Moore RA, McQuay HJ (1997b), Efficacy, dose- response, and safety of ondansetron in prevention of postoperative nausea and vomiting: A quantitative systematic review of randomized placebo-controlled trials, Anesthesiology 87: 1277-1289

21 WHO EML – Anti-emetics – January 2009 o Tramer MR, Reynolds DJM, Moore RA, McQuay HJ (1997c), Impact of covert duplicate publication on meta-analysis: A case study, British Medical Journal 315: 635-640 o Warren A, King L (2008), A review of the efficacy of dexamethasone in the prevention of postoperative nausea and vomiting, Journal of Clinical Nursing 17: 58-68 o WHO Model List of Essential Medicines for Children (October 2007). http://www.who.int/medicines/publications/essentialmedicines/en/index.html [Accessed on 13th January 2009]

22 WHO EML – Anti-emetics – January 2009

Appendix A Search strategies were used to identify relevant studies of anti-emetics for the management of postoperative nausea and vomiting in children. The MEDLINE and EMBASE databases were search using the EMBASE.com interface. The PREMEDLINE database was search using the PUBMED interface. The CDSR, DARE, CMR, HTA, CRG and NHSEED databases were search using the Cochrane library interface. The search results for EMBASE.com are presented in Table A.1, the results of the Cochrane library are presented in Table A.2 and the results from PUBMED are presented in Table A.3.

Table A. 1: Anti-emetics for the management of postoperative nausea and vomiting in children. EMBASE.com search strategy (21st January 2009) # Keywords Results 1 'postoperative nausea and vomiting'/exp 2,718 2 (postoperative:ti,ab OR (post:ti,ab AND operative: ti,ab)) 277,636 3 nausea:ti,ab OR vomiting:ti,ab 51,660 4 #2 AND #3 6,556 5 ponv:ti,ab 958 6 #1 OR #4 OR #5 7,779 7 'antiemetic agent'/exp 123,444 8 'anti emetic':ti,ab OR 'antiemetic':ti,ab OR 'anti-emetic':ti,ab 4,635 'alizapride'/exp OR 'betamethasone'/exp OR 'chlorpromazine'/exp OR 'cimetidine'/exp OR 'cinnarizine'/exp OR 'clebopride'/exp OR 'cyclizine'/exp OR 'dexamethasone'/exp OR 'dimenhydrinate'/exp OR 'dixyrazine'/exp OR 'dolasetron'/exp OR 'domperidone'/exp OR 'droperidol'/exp OR 'famotidine'/exp OR 'granisetron'/exp OR 9 'haloperidol'/exp OR 'hyoscine'/exp OR 'itasetron'/exp OR 342,453 'meclozine'/exp OR 'methylprednisolone'/exp OR 'metoclopramide'/exp OR 'ondansetron'/exp OR 'palonosetron'/exp OR 'perphenazine'/exp OR 'prednisolone'/exp OR 'prochlorperazine'/exp OR 'promethazine'/exp OR 'ramosetron'/exp OR 'ranitidine'/exp OR 'sulpiride'/exp OR 'tiapride'/exp OR 'trifluoperazine'/exp OR 'tropisetron'/exp 10 #7 OR #8 OR #9 367,304 11 #6 AND #10 2,935 12 'meta analysis'/exp OR 'systematic review'/exp 53,393 13 ((meta:ti,ab AND anal*:ti,ab) OR metaanal*:ti,ab) 31,208 14 cochrane:ti,ab OR medline:ti,ab OR embase:ti,ab 37,462 15 systematic AND review*:ti,ab 40,976 16 #12 OR #13 OR #14 OR #15 107,010 17 #11 AND #16 169

23 WHO EML – Anti-emetics – January 2009

Table A. 2: Anti-emetics for the management of postoperative nausea and vomiting in children, Cochrane library search strategy (21st January 2009) # Keywords Results 1 MeSH descriptor Postoperative Nausea and Vomiting explode all trees 990 2 (postoperative OR (post AND operative)) 39,458 3 (nausea OR vomiting) 15,736 4 (#2 AND #3) 4,138 5 (PONV) 615 6 (#1 OR #4 OR #5) 4,158 7 MeSH descriptor Antiemetics explode all trees 9,502 (alizapride OR betamethasone OR chlorpromazine OR cimetidine OR cinnarizine OR clebopride OR cyclizine OR dexamethasone OR dimenhydrinate OR dixyrazine OR dolasetron OR domperidone OR droperidol OR famotidine OR granisetron OR haloperidol OR hyoscine 8 22,137 OR itasetron OR meclozine OR methylprednisolone OR metoclopramide OR ondansetron OR palonosetron OR perphenazine OR prednisolone OR prochlorperazine OR promethazine OR ramosetron OR ranitidine OR sulpiride OR tiapride OR trifluoperazine OR tropisetron) 9 (#7 OR #8) 24,641 10 (#6 AND #9) 1,379 11 (#10 limited to CDSR, DARE, CMR, HTA, CRG, NHSEED) 124

Table A. 3: Anti-emetics for the management of postoperative nausea and vomiting in children, Pubmed search strategy (21st January 2009) # Keywords Results 1 "postoperative" [tiab] OR "post operative" [tiab] OR "post-operative" [tiab] 241,593 2 nausea [tiab] OR vomiting [tiab] 46,352 3 #1 and #2 5,649 4 PONV [tiab] 791 5 #3 or #4 5,693 6 "anti emetic" [tiab] OR "antiemetic" [tiab] OR "anti-emetic" [tiab] 4,150 (alizapride OR betamethasone OR chlorpromazine OR cimetidine OR cinnarizine OR clebopride OR cyclizine OR dexamethasone OR dimenhydrinate OR dixyrazine OR dolasetron OR domperidone OR droperidol OR famotidine OR granisetron OR haloperidol OR hyoscine 7 182,058 OR itasetron OR meclozine OR methylprednisolone OR metoclopramide OR ondansetron OR palonosetron OR perphenazine OR prednisolone OR prochlorperazine OR promethazine OR ramosetron OR ranitidine OR sulpiride OR tiapride OR trifluoperazine OR tropisetron) 8 #6 or #7 183,628 9 #5 and #8 1,550 10 #5 and #8 Limits: MEDLINE 1,497 11 #9 NOT #10 53

24 Appendix B 22 relevant systematic reviews were included that assessed the evidence for the use of anti-emetics in the management of postoperative nausea and vomiting.

o 7 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 7 reviews evaluating the effectiveness of anti-emetics in the prevention of postoperative nausea and vomiting in both adults and children (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 2 reviews evaluating the effectiveness of anti-emetics in the treatment of established postoperative nausea and vomiting in both adults and children (Kazemi et al 2001, Tramer et al 1997) o 6 reviews evaluating the effectiveness of anti-emetics in the prevention of postoperative nausea and vomiting in both adults and children (did not provide a separate analysis of children studies) (Carlisle & Stevenson 2006, Eberhardt et al 2000, Habib et al 2004, Kranke et al 2002b, Leslie & Gan 2006, Tramer et al 1997b).

The characteristics of these reviews are summarised in Table B.1.

Table B. 1: Characteristics of systematic reviews assessing the effectiveness of anti-emetic medications Review (year) Research aim Methodology Key results/conclusions Children Bolton (2006) A literature search was conducted using Medline, POV up to 24 hours: Embase and Cochrane databases. Reference lists - Children, dexamethasone vs. placebo (9 studies) To review the literature on of reviews/included articles were searched. [OR 0.23, 95% CI 0.16–0.33] [RR 0.48, 95% CI 0.40–0.57] interventions used in the Additional references identified through manual - Children, ondansetron vs. placebo (10 studies) prevention of POV in searching of specific journals. English-language [OR 0.36, 95% CI 0.29–0.46] children after tonsillectomy restriction. - Children, granisetron vs. placebo (3 studies) (with or without [OR 0.11, 95% CI 0.06–0.19] adenoidectomy) Literature search was conducted in September - Children, tropisetron vs. placebo (2 studies) 2003. [OR 0.15, 95% CI 0.06–0.35] - Children, dolasetron vs. placebo (1 study) Studies with the following characteristics were [OR 0.25, 95% CI 0.1–0.59] included: RCT; placebo/no-treatment control; - Children, metoclopramide vs placebo (4 studies) paediatric patients undergoing tonsillectomy with [OR 0.51, 95% CI 0.34–0.77] or without adenoidectomy; prophylactic - Children, 5HT3 vs. placebo (15 studies) WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions metoclopramide, dimenhydrinate, droperidol, [OR 0.12, 95% CI 0.07-0.20] perphenazine, ondansetron, granisetron, - Children, dimenhydrinate vs. placebo (1 study) tropisetron, dolasetron, midazolam, [OR 0.84, 95% CI 0.20–3.65] dexamethasone, gastric aspiration, acupuncture; - Children, perphenazine vs. placebo (1 study) dichotomous outcomes (PONV) up to 24 hours. [OR 0.50, 95% CI 0.31–0.82] - Children, droperidol vs. placebo (1 study) Studies were evaluated by two independent [OR 0.99, 95% CI 0.44–2.22] reviewers. A limited assessment of the quality of included studies was undertaken. Conclusion: Dexamethasone, granisetron, ondansetron, tropisetron, dolasetron are effective in preventing POV. There is insufficient evidence that dimenhydrinate, perphenazine or droperidol are effective in preventing POV. Engelman (2008) A literature search was conducted using the Any PONV: Pubmed database. Reference lists of - Children, ondansetron (0.1–0.15 mg/kg) vs. placebo (14 To calculate the various reviews/included articles were searched. Unclear studies) [OR 0.37, 95% CI 0.35–0.39] [RR 0.54, 95% CI effect sizes for each if language restrictions were applied. 0.51–0.56] treatment recommended in - Children, tropisetron (0.1-0.2 mg/kg) vs. placebo (5 studies) the current paediatric Unclear when literature search was conducted. [OR 0.17, 95% CI 0.13-0.22] [RR 0.41, 95% CI 0.34-0.50] guidelines - Dolasetron (0.35 mg/kg i.v. or 1.8 mg/kg oral) vs. placebo (2 Studies with the following characteristics were studies) [OR 0.16, 95% CI 0.09-0.27] [RR 0.39, 95% CI 0.25- included: controlled trials (did not need to be 0.56] RCT); placebo control for single drug treatments, - Children, granisetron (0.040 mg/kg) vs. placebo (3 studies) active control (one component of combination [OR 0.16, 95% CI 0.10-0.20] [RR 0.31, 95% CI 0.20-0.45] treatment) or placebo for combination drug - Children, dexamethasone (0.050-1.0 mg/kg) vs. placebo (13 treatments; paediatric patients undergoing studies) [OR 0.31, 95% CI 0.28-0.34] [RR 0.53 95% CI 0.49- surgery; prophylactic ondansetron, tropisetron, 0.56] granisetron, dolasetron, dexamethasone, - Children, droperidol (5-25 mcg/kg) vs. placebo (3 studies) droperidol (5-25 mcg/kg), ondansetron plus [OR 0.48, 95% CI 0.37-0.61] [RR 0.62, 95% CI 0.52-0.74] dexamethasone, ondansetron plus droperidol, - Children, ondansetron (0.05-0.15 mg/kg) plus tropisetron plus dexamethasone, dolasetron plus dexamethasone (0.1-1 mg/kg) vs. ondansetron or dexamethasone, and granisetron plus dexamethasone alone (5 studies) [OR 0.25, 95% CI 0.20- dexamethasone; dichotomous outcomes (PONV, 0.31] [RR 0.33, 95% CI 0.27-0.40] use of rescue medications) - Children, tropisetron (0.1 mg/kg) plus dexamethasone (0.15 or 0.50 mg/kg) vs. tropisetron (2 studies) [OR 0.31, 95% CI Studies were evaluated by an unknown number of 0.20-0.49] [RR 0.49, 95% 0.34-0.67] reviewers. No assessment of quality was - Children, dolasetron (0.5 mg/kg) plus dexamethasone (1.0 described. mg/kg) vs. dexamethasone (1 study) [OR 0.29, 95% CI 0.13- 0.67] [RR 0.48, 95% CI 0.25-0.82]

26 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions - Children, ondansetron (0.15 mg/kg) plus droperidol (25 mcg/kg) vs. placebo (1 study) [OR 0.09, 95% CI 0.04-0.23] [RR 0.22, 95% CI 0.10-0.45] - Children, ondansetron (0.15 mg/kg) plus dexamethasone (0.2 mg/kg) vs. placebo (1 study) [OR 0.12, 95% CI 0.03- 0.44] [RR 0.22, 95% CI 0.07-0.61] - Children, granisetron (0.04 mg/kg) plus dexamethasone (0.15 mg/kg) vs. placebo (1 study) [OR 0.05, 95% CI 0.001- 0.31] [RR 0.10, 95% CI 0.02-0.47] - Children, ondansetron plus dexamethasone vs. placebo (indirect comparison) [RR 0.17, 95% CI 0.14-0.21] - Children, tropisetron plus dexamethasone vs. placebo (indirect comparison) [RR 0.20, 95% CI 0.14-0.30] - Children, dolasetron plus dexamethasone vs. placebo (indirect comparison) [RR 0.21, 95% CI 0.12-0.39]

Conclusion: Droperidol, dexamethasone, granisetron, ondansetron, tropisetron, dolasetron are effective in preventing PONV. The combination of a 5HT3 antagonist and dexamethasone may be more effective than either component alone. Goldman (2000) A literature search was conducted using the Any POV: Medline database. Reference lists of - Children, dexamethasone vs. placebo (5 studies) [RD 0.73, To determine the reviews/included articles were searched. No 95% CI 0.58–0.88] quantitative impact of language restrictions. intravenous Conclusion: Dexamethasone is effective in preventing POV. dexamethasone on Literature search was conducted in 1998. recovery after tonsillectomy Studies with the following characteristics were included: RCT; placebo/no-treatment control; paediatric patients undergoing tonsillectomy; prophylactic i.v. dexamethasone administered peri-operatively; dichotomous outcomes (PONV) with complete data (numerator and denominator) available.

Studies were evaluated by two independent reviewers. A limited assessment of the quality of

27 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions included studies was undertaken. Lim (1999) A literature search was conducted using Medline, POV up to 24h: Embase and Globe databases. No language - Children, ondansetron vs. droperidol (9 studies) [RR 0.67, To determine the pooled restrictions. Reference lists of reviews/included 95% CI 0.49–0.90] relative risk of ondansetron articles were searched. - Children, ondansetron vs. metoclopramide (8 studies) [RR relative to droperidol and 0.56, 95% CI 0.44–0.71] relative to metoclopramide Unclear when literature search was conducted. PONV up to 24h: in the prevention of PONV - Children, ondansetron vs. droperidol (13 studies) [RR 0.70, Studies with the following characteristics were 95% CI 0.53–0.92] included: RCT; active control; paediatric patients undergoing surgery; prophylactic metoclopramide, Conclusion: Ondansetron is more effective than droperidol, ondansetron (at least two drugs); metoclopramide or droperidol in preventing PONV. dichotomous outcomes (PONV)

Studies were evaluated by two independent reviewers. A limited assessment of the quality of included studies was undertaken. Steward (2001) A literature search was conducted using Medline POV up to 24h: and Cochrane databases. Reference lists of - Children, dexamethasone vs. placebo (7 studies) [RR 0.55, To determine whether a reviews/included articles were searched. Experts 95% CI 0.41–0.74] single intraoperative contacted for additional references. Authors dose of dexamethasone contacted for additional information. No language Conclusion: Dexamethasone is effective in preventing POV. reduces morbidity following restrictions. paediatric tonsillectomy or adenotonsillectomy Unclear when literature search was conducted.

Studies with the following characteristics were included: RCT; placebo/no-treatment control; paediatric patients undergoing tonsillectomy; prophylactic i.v. dexamethasone administered intra-operatively; dichotomous outcomes (PONV, return to soft or solid diet, pain).

Studies were evaluated by an unknown number of reviewers. No assessment of quality was described. Steward (2003) A literature search was conducted using Medline, POV up to 24h: Embase and Cochrane databases. Reference lists - Children, dexamethasone vs. placebo (8 studies) [RR 0.54,

28 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions To assess the clinical of reviews/included articles were searched. 95% CI 0.42–0.69] efficacy of a single Experts contacted for additional references. No intraoperative dose of language restrictions. Conclusion: Dexamethasone is effective in preventing POV. dexamethasone in reducing post-tonsillectomy morbidity Literature search was conducted in February 2002.

Studies with the following characteristics were included: RCT; placebo/no-treatment control; paediatric patients undergoing tonsillectomy or adenotonsillectomy; prophylactic i.v. corticosteroid administered intra-operatively; dichotomous outcomes (PONV, return to soft or solid diet, pain).

Studies were evaluated by one independent reviewer. A limited assessment of the quality of included studies was undertaken. Tramer (1995) A literature search was conducted using the POV up to 6 h: Medline database. Reference lists of - Children, droperidol 10 mcg/kg vs. placebo (1 study) To assess the effectiveness reviews/included articles were searched. No [OR 1.6, 95% CI 0.4–7.2] and safety of anti-emetics language restrictions. - Children, droperidol 20 mcg/kg vs. placebo (1 study) used in strabismus surgery [OR 1.9, 95% CI 0.7–5] for the prevention of PONV Literature search was conducted in December - Children, droperidol 50 mcg/kg vs. placebo (2 studies) 1994. [OR 1.5, 95% CI 0.7–3.2] - Children, droperidol 75 mcg/kg vs. placebo (10 studies) Studies with the following characteristics were [OR 3.3, 95% CI 2.4–4.7] included: RCT; placebo/no-treatment control; - Children, metoclopramide 0.10 mg/kg vs. placebo (1 study) paediatric patients undergoing strabismus [OR 3.9, 95% CI 0.7–20.9] surgery; prophylactic interventions; dichotomous - Children, metoclopramide 0.15 mg/kg vs. placebo (3 outcomes (PONV); abstracts/unpublished data studies) [OR 2.8, 95% CI 1.7–4.6] were excluded. - Children, metoclopramide 0.25 mg/kg vs. placebo (2 studies) [OR 5.0, 95% CI 2.4–10.3] Studies were evaluated by multiple independent - Children, dixyrazine 0.25 mg/kg vs. placebo (2 studies) reviewers. A detailed assessment of quality was [OR 5.6, 95% CI 1.5–20] undertaken - Children, ondansetron 0.15 mg/kg vs. placebo (1 study) [OR 6.5, 95% CI 2.2–19.5] - Children, atropine 10 mcg/kg vs. placebo (1 study)

29 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions [OR 1.3, 95% CI 0.3–4.7] - Children, lorazepam 10 mcg/kg vs. placebo (1 study) [OR 1.5, 95% CI 0.6–3.9] POV up to 48h: - Children, droperidol 50 mcg/kg vs. placebo (2 studies) [OR 1.3, 95% CI 0.5–3.4] - Children, droperidol 75 mcg/kg vs. placebo (10 studies) [OR 2.5, 95% CI 1.7–3.6] - Children, metoclopramide 0.15 mg/kg vs. placebo (3 studies) [OR 6.6, 95% CI 1.7–25.1] - Children, metoclopramide 0.25 mg/kg vs. placebo (2 studies) [OR 1.7, 95% CI 0.6–4.8] - Children, dixyrazine 0.25 mg/kg vs. placebo (2 studies) [OR 5.4, 95% CI 2.8–10.2] - Children, ondansetron 0.15 mg/kg vs. placebo (1 study) [OR 4.2, 95% CI 1.6–11.6] - Children, ligocaine 2 mg/kg vs. placebo (1 study) [OR 3.9, 95% CI 1.2–12.2] - Children, hyoscine 0.375-0.75 mg vs. placebo (1 study) [OR 4.2, 95% CI 1.3–13.7] - Children, atropine 10 mcg/kg vs. placebo (1 study) [OR 0.4, 95% CI 0.1–0.2] - Children, lorazepam 10 mcg/kg vs. placebo (1 study) [OR 1.7, 95% CI 0.7–4.1]

With droperidol (75 mcg/kg) fewer than one child in 100 may have an extrapyramidal reaction and 16 may have minor adverse effects.

Conclusion: Metoclopramide (0.15 and 0.25 mg/kg) is effective for preventing early POV while droperidol (75 mcg/kg) is effective in preventing both early and late POV. Mixed population (adults and children) Carlisle (2006) A literature search was conducted using Medline, Review did not present a separate analysis of children Embase, Cochrane, Cinahl, Amed, Sigle, ISI studies. To determine the efficacy WOS, Lilac and Ingenta databases. No language and safety of drugs used in restrictions. Conclusion: Cyclizine, droperidol, granisetron, the prevention of PONV metoclopramide, ondansetron, tropisetron, dolasetron and

30 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions Literature search was conducted in May 2004. dexamethasone are effective in preventing PONV.

Studies with the following characteristics were included: RCT, active control or placebo/no- treatment control; unspecified patient population; prophylactic interventions; dichotomous outcomes (PONV, use of rescue medications)

Studies were evaluated by two independent reviewers. A detailed assessment of quality was undertaken. Domino (1999) A literature search was conducted using the Any POV: Medline database. Reference lists of - Children, ondansetron vs metoclopramide (6 studies) [OR To determine the relative reviews/included articles were searched. 0.33, 95% CI 0.27–0.39] efficacy and safety of Additional references identified through manual - Children, ondansetron vs droperidol (9 studies) [OR 0.49, ondansetron, searching of specific journals. English-language 95% CI 0.30–0.80] metoclopramide, and restriction. - Children, droperidol vs metoclopramide (7 studies) [OR droperidol in the prevention 0.63, 95% CI 0.36–1.10] of PONV Literature search was conducted in May 1998. The overall risk of adverse effects was not different among Studies with the following characteristics were drug combinations. included: RCT; active control; surgery patients with general anaesthesia; prophylactic Conclusion: Ondansetron and droperidol are more effective metoclopramide, droperidol, ondansetron (at least than metoclopramide in preventing POV. two drugs); dichotomous outcomes (PONV, use of rescue medications); abstracts/unpublished data were excluded.

Studies were evaluated by two independent reviewers. A detailed assessment of quality was undertaken. Eberhardt (2000) A literature search was conducted using Medline, Review did not present a separate analysis of children Embase and Cochrane databases. Reference lists studies. To determine the relative of reviews/included articles were searched. No efficacy of 5-HT3 language restrictions. Conclusion: The combination of a 5HT3 antagonist and antagonists or droperidol droperidol may be more effective than either component alone versus the Literature search was conducted in December alone. combination of both drugs 1999.

31 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions in the prevention of PONV Studies with the following characteristics were included: RCT; active control; unspecified patient population; prophylactic 5-HT3 antagonists or droperidol alone versus the combination of both drugs; dichotomous outcomes (PONV); abstracts/ unpublished data were excluded.

Studies were evaluated by two independent reviewers. No assessment of quality was described. Figueredo (1998) A literature search was conducted using the POV up to 8h: Medline database. Reference lists of - Children, ondansetron 0.10 mg/kg vs. placebo (3 studies) To assess the efficacy and reviews/included articles were searched. No [OR 4.54, 95% CI 2.68–7.71] safety (incidence of language restrictions. - Children, ondansetron 0.15 mg/kg vs. placebo (5 studies) headache) of ondansetron [OR 5.14, 95% CI 3.23–8.17] in the prevention of POV Literature search was conducted in July 1997. POV up to 24h: - Children, ondansetron 0.05 mg/kg vs. placebo (2 studies) Studies with the following characteristics were [OR 2.36, 95% CI 0.49–11.39] included: RCT; placebo/no-treatment control; - Children, ondansetron 0.10 mg/kg vs. placebo (5 studies) surgery patients with general anaesthesia; [OR 2.87, 95% CI 1.63–5.04] prophylactic ondansetron; dichotomous outcomes - Children, ondansetron 0.15 mg/kg vs. placebo (5 studies) (PONV); abstracts/unpublished data were [OR 3.02, 95% CI 1.99–4.59] excluded. The overall incidence of headache was 7.05% in ondansetron Studies were evaluated by an unknown number of groups versus 6.16% in placebo groups. reviewers. No assessment of quality was undertaken. Conclusion: Ondansetron is effective in preventing POV. Habib (2004) A literature search was conducted using Medline, Review did not present a separate analysis of children Embase and Cochrane databases. Reference lists studies. To compare the efficacy of reviews/included articles were searched. No and side effects of language restrictions. Conclusion: The combination of a 5HT3 antagonist with combining one of the 5-HT3 droperidol or dexamethasone is more effective than 5HT3 antagonists with droperidol Literature search was conducted in April 2003. antagonists alone. or dexamethasone in the prevention of PONV Studies with the following characteristics were included: RCT; active control; unspecified patient population; prophylactic 5-HT3 antagonists alone

32 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions versus the combination of 5-HT3 antagonists with droperidol or dexamethasone; dichotomous outcomes (PONV); abstracts/ unpublished data were excluded.

Studies were evaluated by two independent reviewers. A detailed assessment of quality was undertaken. Henzi (1999) A literature search was conducted using Medline, POV up to 6h: Embase and Cochrane databases. Reference lists - Children, Metoclopramide 0.10 mg/kg i.v. vs. placebo (1 To define the anti-emetic of reviews/included articles were searched. study) [RB 1.17, 95% CI 0.97–1.41] efficiency of Additional references identified through manual - Children, Metoclopramide 0.12 mg/kg i.v. vs. placebo (1 metoclopramide compared searching of specific journals. Manufacturers of study) [RB 0.83, 95% CI 0.62–1.12] with placebo or no metoclopramide were also contacted. No - Children, Metoclopramide 0.15 mg/kg i.v. vs. placebo (3 treatment in the prevention language restrictions. studies) [RB 1.71, 95% CI 1.33–2.19] of PONV; to establish dose- - Children, Metoclopramide 0.20 mg/kg i.v. vs. placebo (1 responsiveness; to Literature search was conducted in June 1998. study) [RB 1.11, 95% CI 0.80–1.54] compare anti-nausea with - Children, Metoclopramide 0.25 mg/kg i.v. vs. placebo (7 anti-vomiting efficacy; to Studies with the following characteristics were studies) [RB 1.44, 95% CI 1.11–1.87] investigate the potential for included: RCT; placebo/no-treatment control; - Children, Metoclopramide 0.50 mg/kg i.v. vs. placebo (2 toxic effects of surgery patients with general anaesthesia or studies) [RB 1.32, 95% CI 0.89–1.96] metoclopramide in the combined spinal and general anaesthesia; PON up to 6h: surgical setting prophylactic metoclopramide; dichotomous - Children, Metoclopramide 0.12 mg/kg i.v. vs. placebo (1 outcomes (PONV); abstracts/unpublished data study) [RB 1.00, 95% CI 0.81–1.23] were excluded. - Children, Metoclopramide 0.20 mg/kg i.v. vs. placebo (1 study) [RB 1.25, 95% CI 0.81–1.94] Studies were evaluated by multiple independent POV up to 48h: reviewers. A detailed assessment of quality was - Children, Metoclopramide 0.15 mg/kg i.v. vs. placebo (2 undertaken studies) [RB 2.28, 95% CI 1.37–3.78] - Children, Metoclopramide 0.15 mg/kg oral vs. placebo (1 study) [RB 0.86, 95% CI 0.50–1.48] PON up to 48h: - Children, Metoclopramide 0.25 mg/kg i.v. vs. placebo (1 study) [RB 1.37, 95% CI 0.92–2.04] PONV up to 48h: - Children, Metoclopramide 0.10 mg/kg i.v. vs. placebo (1 study) [RB 1.08, 95% CI 0.65–1.80]

33 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions Minor drug-related adverse effects (sedation, dizziness, drowsiness) were not significantly associated with metoclopramide

Conclusion: Metoclopramide is not effective in preventing PONV. Henzi (2000) A literature search was conducted using Medline, POV up to 6 hours: Embase and Cochrane databases. Reference lists - Children, dexamethasone 1–1.5 mg/kg i.v. vs. placebo (3 To define the antiemetic of reviews/included articles were searched. studies) [RB 1.17, 95% CI 1.02–1.34] efficacy and safety Additional references identified through manual - Children, dexamethasone 150 mcg/kg i.v. vs. perphenazine of dexamethasone in the searching of specific journals. No language 70 mcg/kg i.v. (1 study) [RB 0.74, 95% CI 0.63-0.86] prevention of PONV restrictions. POV up to 24 hours: - Children, dexamethasone 0.5 mg/kg i.v. vs. placebo (1 Literature search was conducted in April 1999. study) [RB 1.03, 95% CI 0.91–1.18] - Children, dexamethasone 1–1.5 mg/kg i.v. vs. placebo (3 Studies with the following characteristics were studies) [RB 1.80, 95% CI 1.47–2.21] included: RCT, active control or placebo/no- - Children, dexamethasone 4 mg plus granisetron 40 mcg/kg treatment control; surgery patients with general i.v. vs. granisetron 40 mcg/kg i.v. (1 study) [RB 1.27, 95% CI anaesthesia; prophylactic dexamethasone; 1.01–1.61] dichotomous outcomes (PONV); abstracts/unpublished data were excluded. Adverse effects were most frequently reported for the association of dexamethasone with a 5-HT3 antagonist. Studies were evaluated by multiple independent Adverse effects were headache, dizziness, drowsiness and reviewers. A detailed assessment of quality was sedation, constipation, and muscle pain. There was no undertaken statistically significant difference between dexamethasone, 5- HT3 receptor antagonists, and placebo for these adverse effects.

Conclusion: Dexamethasone is effective in preventing POV. Henzi (2000b) A literature search was conducted using Medline, POV up to 6 hours: Embase and Cochrane databases. Reference lists - Children, droperidol 10–20 mcg/kg i.v. vs. placebo (3 To estimate the efficacy of reviews/included articles were searched. studies) [RR 1.17, 95% CI 1.06–1.29] and harm produced by Additional references identified through manual - Children, droperidol 40–50 mcg/kg i.v. vs. placebo (3 droperidol in the prevention searching of specific journals. No language studies) [RR 1.34, 95% CI 1.09–1.64] of PONV restrictions. - Children, droperidol 75 mcg/kg i.v. vs. placebo (11 studies) [RR 1.47, 95% CI 1.20–1.82] Literature search was conducted in May 1999. - Children, droperidol 50 mcg/kg i.m. vs. placebo (1 study) [RR 1.16, 95% CI 1.01–1.34]

34 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions Studies with the following characteristics were - Children, droperidol 200 mcg/kg i.m. vs. placebo (1 study) included: RCT, active control or placebo/no- [RR 1.18, 95% CI 1.05–1.32] treatment control; surgery patients with general - Children, droperidol 200 mcg/kg oral vs. placebo (1 study) anaesthesia or combined spinal and general [RR 1.44, 95% CI 1.13–1.85] anaesthesia; prophylactic droperidol; dichotomous POV up to 24 hours: outcomes (PONV); abstracts/ unpublished data - Children, droperidol 5–20 mcg/kg i.v. vs. placebo (2 studies) were excluded. [RR 1.22, 95% CI 1.07–1.39] - Children, droperidol 50 mcg/kg i.v. vs. placebo (2 studies) Studies were evaluated by multiple independent [RR 1.51, 95% CI 1.09–2.11] reviewers. A detailed assessment of quality was - Children, droperidol 75 mcg/kg i.v. vs. placebo (10 studies) undertaken [RR 1.55, 95% CI 1.17–2.06] - Children, droperidol 300 mcg/kg oral vs. placebo (1 study) [RR 1.66, 95% CI 1.09–2.53]

Two children had extrapyramidal symptoms with droperidol (NNH = 91). Sedation and drowsiness were dose dependent. Droperidol prevented postoperative headache.

Conclusion: Droperidol is effective in preventing POV. Kazemi (2001) A literature search was conducted using Medline, POV up to 6 hours: Embase and Cochrane databases. Reference lists - Children, ondansetron 0.1 mg/kg vs. placebo (1 study) To review the literature on of reviews/included articles were searched. [RR 2.27, 95% CI 1.83–2.81] interventions used in the Additional references identified through manual - Children, isopropyl alcohol vs. placebo (1 study) treatment of established searching of specific journals. Authors contacted [RR 3.33, 95% CI 0.79–14.0] PONV symptoms; to test for for additional information. No language PON up to 6 hours: dose-responsiveness for restrictions. - Children, isopropyl alcohol vs. placebo (1 study) each drug, and to estimate [RR 2.14, 95% CI 1.24–3.69] relative efficacy and Literature search was conducted in August 2000. POV up to 24 hours: likelihood for harm of - Children, ondansetron 0.1 mg/kg vs. placebo (1 study) the various treatments. Studies with the following characteristics were [RR 3.14, 95% CI 2.21–4.48] included: RCT; active control or placebo/no- treatment control; vomiting or nauseated Comparisons with active controls were not analysed in the postoperative patients; therapeutic treatments; systematic review. dichotomous outcomes (PONV); abstracts/ unpublished data were excluded. The most frequently reported adverse effect with 5-HT3 antagonists was headache. There was some evidence of Studies were evaluated by multiple independent dose-responsiveness. reviewers. A detailed assessment of quality was

35 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions undertaken Conclusion: 5-HT3 antagonists are effective in preventing PONV. Kranke (2002) A literature search was conducted using Medline, PONV up to 48 hours: Embase and Cochrane databases. Reference lists - Children, dimenhydrinate single 0.5–2.2 mg/kg i.v./i.m. dose To evaluate the quantitative of reviews/included articles were searched. vs. placebo (3 studies) [RB 1.8, 95% CI 1.31–2.47] effect of dimenhydrinate in Additional references identified through manual - Children, dimenhydrinate single 2–3 mg/kg rectal dose vs. the prevention of PONV searching of specific journals. No language placebo (2 studies) [RB 1.7, 95% CI 1.16–2.53] restrictions. Conclusion: Dimenhydrinate is effective in preventing Literature search was conducted in June 2001. PONV.

Studies with the following characteristics were included: RCT; placebo/no-treatment control; unspecified patient population; prophylactic dimenhydrinate, diphenhydramine; dichotomous outcomes (PONV); abstracts/ unpublished data were excluded.

Studies were evaluated by two independent reviewers. A detailed assessment of quality was undertaken Kranke (2002b) A literature search was conducted using Medline, Review did not present a separate analysis of children Embase and Cochrane databases. Manufacturers studies. To evaluate the efficacy of hyoscine were also contacted. Unclear if and harm of transdermal language restrictions were applied. Conclusion: Hyoscine is effective in preventing PONV. hyoscine in the prevention of PONV Literature search was conducted in September 2001.

Studies with the following characteristics were included: RCT; placebo/no-treatment control; surgery patients with general or regional anaesthesia; prophylactic transdermal hyoscine; dichotomous outcomes (PONV, use of rescue medications); abstracts were excluded.

Studies were evaluated by an unknown number of reviewers. A detailed assessment of quality was

36 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions undertaken Leslie (2006) A literature search was conducted using the Review did not present a separate analysis of children Medline database. Unclear if language restrictions studies. To assess the safety were applied. profiles of 5HT3 antagonist Conclusion: The combination of a serotonin 5HT3 antagonist monotherapy and Literature search was conducted in September with droperidol or dexamethasone has a similar safety profile combination therapy with a 2005. to each therapy alone. steroid or droperidol in the prevention of PONV Studies with the following characteristics were included: RCT; active control; prophylactic serotonin 5HT3 antagonists as monotherapy compared to dexamethasone or droperidol or 5HT3 combination therapy (with dexamethasone or droperidol) compared to dexamethasone, droperidol or 5HT3 antagonist alone; dichotomous outcomes (adverse events).

Studies were evaluated by an unknown number of reviewers. No assessment of quality was described. Tramer (1997) A literature search was conducted using the PONV up to 6 hours: Medline database. Reference lists of - Children, ondansetron 100 mcg/kg vs. droperidol 20 mcg/kg To test the evidence for a reviews/included articles were searched. (1 study) [OR 0.6, 95% CI 0.1–3.4] dose-response with Additional references identified through manual ondansetron for the searching of specific journals. No language Conclusion: Ondansetron is as effective as droperidol in treatment of established restrictions. treating PONV PONV symptoms and to determine whether Literature search was conducted in January 1996. differences in efficacy between doses are of Studies with the following characteristics were clinical relevance included: RCT; active control or placebo/no- treatment control; vomiting or nauseated postoperative patients; therapeutic ondansetron; dichotomous outcomes (PONV); abstracts/ unpublished data were excluded.

Studies were evaluated by multiple independent reviewers. A detailed assessment of quality was

37 WHO EML – anti-emetics – October 2008

Review (year) Research aim Methodology Key results/conclusions undertaken Tramer (1997b) A literature search was conducted using the Review did not present a separate analysis of children Medline, Biological Abstracts and Embase studies. To define ondansetron's databases. Reference lists of reviews/included antiemetic efficacy articles were searched. Additional references Conclusion: Ondansetron is effective in preventing POV. compared with placebo or identified through manual searching of specific no treatment in the journals. No language restrictions. prevention of PONV; to test dose-response evidence; to Studies with the following characteristics were identify the optimal dose for included: RCT; placebo/no-treatment control; oral and intravenous routes; surgery patients with general anaesthesia; to compare anti-nausea prophylactic ondansetron; dichotomous outcomes with anti-vomiting (PONV); abstracts/unpublished data were efficacies; to investigate excluded. ondansetron's potential for toxic effects in the surgical Studies were evaluated by multiple independent setting. reviewers. A detailed assessment of quality was undertaken Warren (2008) A literature search was conducted using the 4 studies in children reported control group incidences of Medline, Ovid, CINAHL and Cochrane databases. overall postoperative vomiting of between 51% and 88%. To determine if No language restrictions. English-language Overall, following administration of dexamethasone the dexamethasone has an restriction. incidence of vomiting was reduced to a range from 20%–48% effect in the prevention of Unclear when literature search was conducted. PONV compared with placebo Studies with the following characteristics were included: RCT; placebo/no-treatment control; unspecified patient population; prophylactic dexamethasone; dichotomous outcomes (PONV); article published within 10 years of literature search.

Studies were evaluated by an unknown number of reviewers. A limited assessment of the quality of included studies was undertaken. Abbreviations: CI, confidence interval; NNH, number needed to harm; OR, odds ratio; PON, postoperative nausea; PONV, postoperative nausea and vomiting; POV, postoperative vomiting; RB, risk benefit; RCT, randomised controlled trial; RD, risk difference; RR, relative risk.

38 Appendix C

Table C.1: Dosing information SAMBA guidelines dosing Supplementary dosing Drug information information

Dose Maximal dose Dose Maximal dose Dimenhydrinate 0.5 mg/kg 25 mg - - Metoclopramide - - 0.1–0.5 mg/kg - Perphenazine 0.07 mg/kg 5 mg - - 0.010–0.015 Droperidol 1.25 mg - - mg/kg Dixyrazine - - 0.25 mg/kg - 0.05–0.10 Ondansetron 4 mg - - mg/kg Granisetron 0.04 mg/kg 0.6 mg - - Dolasetron 0.35 mg/kg 12.5 mg - - Tropisetron 0.1 mg/kg 2 mg - - Dexamethasone 0.15 mg/kg 5 mg - - Hyoscine - - 0.375-0.75 mg - (transdermal) Source: Dosing details for dimenhydrinate, perphenazine, droperidol, ondansetron, granisetron, dolasetron, tropisetron and dexamethasone are based on current guidelines for the management of postoperative nausea and vomiting in children (Gan et al 2007). The treatment details for metoclopramide are based on the range of doses used in the paediatric trials (Henzi et al 1999). The treatment details for dixyrazine are based on DRUGDEX® evaluations (www.micromedex.com; The treatment details for hyoscine are based on the doses used in paediatric trials (Tramer et al 1995)

WHO EML – anti-emetics – October 2008

Table C.2: Cost of anti-emetic medications Price (US$) Drug Formulation Per International Drug Price Indicator Guide Strength Median supplier price Median buyer price Tablet 50mg $0.0150/tablet $0.0100/mL Injection 50mg/mL NR $0.1290/mL Dimenhydrinate Suppository 50mg NR $0.3763/Sup Suppository 100mg NR $0.3332/Sup Tablet 10mg $0.0044/tablet $0.0072/tablet Syrup 5mg/5mL NR $0.0104/mL Metoclopramide Drops 4mg/mL $0.0314/mL NR Injection 5mg/mL $0.0450/mL $0.0777/mL Perphenazine Not listed in International Drug Price Indicator Guide Injection 2.5mg/mL NR $0.4300/mL Droperidol Suppository 100mg NR $0.3332/Sup Dixyrazine Not listed in International Drug Price Indicator Guide Tablet 4mg NR $2.0284/tablet Ondansetron Tablet 8mg NR $7.6716/tablet Injection 2mg/mL NR $2.0194/mL Granisetron Injection 1mg/mL NR $2.9408/mL Dolasetron Not listed in International Drug Price Indicator Guide Tropisetron Injection 1mg/mL NR $2.6882/mL Tablet 0.5mg $0.0068/tablet $0.0182/tablet Dexamethasone Injection 4mg/mL $0.0959/mL $0.0800/mL Injection 5mg/mL $0.0694/mL $0.1250/mL Hyoscine Not listed in International Drug Price Indicator Guide (transdermal) Abbreviations: NR, not reported. Source: International Drug Price Indicator Guide, Search year 2007 (www.erc.msh.org)

40 WHO EML – anti-emetics – October 2008

Appendix D

Table D.1: Regulatory status of anti-emetic medications considered for inclusion Drug International availability/ regulatory status Dimenhydrinate Not currently listed on the WHO essential medicines list for children

FDA: Treatment and prophylaxis of motion sickness (adults, children > 2 years) TGA: Prevention and relief of motion sickness and treatment of vertigo, nausea or vomiting associated with: electroshock therapy, anaesthesia and surgery, labyrinthine disturbances and radiation sickness. Use in children: dimenhydrinate is not recommended for children under 2 years. Metoclopramide Currently listed on the WHO essential medicines list for children as an anti-emetic medication (age restriction: not in neonates)

FDA: Chemotherapy-induced nausea and vomiting (adults); diabetic gastroparesis (adults); gastroesophageal reflux disease (adults); small bowel intestinal intubation (adults, children); postoperative nausea and vomiting (adults); adjunct to radiography of gastrointestinal tract (adults) TGA: Adults (20 years or older): relief of nausea and vomiting associated with migraine, cancer therapy (chemotherapy or radiation), malignant disease, labour, infectious disease and uraemia; control of post operative vomiting; assist in small bowel intubation. Metoclopramide is of little benefit for the prevention or treatment of motion sickness. Young adults and children: Metoclopramide should be restricted to the following conditions when used to treat children and young adults under 20 years of age because of the risk of adverse effects; severe intractable vomiting of known cause; vomiting associated with radiation therapy or intolerance to cytotoxic drugs; assist in small bowel intubation. Use in children: Metoclopramide should not be given to children unless a clear indication has been established for its use. Children are at a greater risk of experiencing adverse reactions to metoclopramide. Perphenazine Not currently listed on the WHO essential medicines list for children

FDA: Nausea and vomiting (adults, children > 12 years); schizophrenia (adults, children > 12 years) TGA: Not approved Droperidol Not currently listed on the WHO essential medicines list for children

FDA: Nausea and vomiting associated with surgical or diagnostic procedures (adults, children > 2 years). TGA: Anaesthesia: droperidol is indicated to produce tranquillisation and to reduce the incidence of nausea and vomiting in surgical and diagnostic procedures; for premedication, induction, and as an adjunct in the maintenance of general and regional anaesthesia; in neuroleptanalgesia in which droperidol is given concurrently with a narcotic analgesic, to aid in producing tranquillity and decreasing anxiety and pain. Psychiatry: the management of severe agitation, hyperactivity, or agressiveness in psychotic disorders, including schizophrenic reaction and the manic type of manic depressive illness, or in disturbed states, such as some types of acute brain syndrome and in nonpsychotic acute excitation states. Use in children: The safety of droperidol in children

41 WHO EML – anti-emetics – October 2008

Drug International availability/ regulatory status younger than 2 years of age has not been established. Therefore, this drug is not recommended in this age group. Dixyrazine Not currently listed on the WHO essential medicines list for children FDA: Not approved TGA: Not approved Ondansetron Not currently listed on the WHO essential medicines list for children

FDA: Chemotherapy-induced nausea and vomiting for highly emetogenic therapy (adults, children > 6 months); chemotherapy- induced nausea and vomiting for moderately emetogenic therapy (adults, children > 6 months; postoperative nausea and vomiting (adults, children > 1 month); radiation-induced nausea and vomiting (adults); TGA: Ondansetron is indicated for the prevention and treatment of nausea and vomiting induced by cytotoxic therapy and radiotherapy. Ondansetron is also indicated for the prevention and treatment of post- operative nausea and vomiting. Use in children: The clinical safety of ondansetron in children under 2 years has not been established. Granisetron Not currently listed on the WHO essential medicines list for children

FDA: Prophylaxis of chemotherapy-induced nausea and vomiting (adults, children > 2 years); postoperative nausea and vomiting (adults); prophylaxis of postoperative nausea and vomiting (adults); radiation- induced nausea and vomiting (adults) TGA: Adults: granisetron is indicated for use in adults for the prevention and treatment of nausea and vomiting induced by cytotoxic therapy. Granisetron injection is also indicated for use in the prevention of nausea and vomiting induced by radiotherapy and for the prevention and treatment of postoperative nausea and vomiting. Children: granisetron is indicated for the prevention of nausea and vomiting induced by cytotoxic chemotherapy. Use in children: There is no experience in the use of granisetron in the prevention and treatment of postoperative nausea and vomiting in children. Dolasetron Not currently listed on the WHO essential medicines list for children

FDA: Prophylaxis of chemotherapy-induced nausea and vomiting (adults, children > 2 years); postoperative nausea and vomiting (adults, children > 2 years); prophylaxis of postoperative nausea and vomiting (adults, children > 2 years) TGA: For use in adults for the prevention and treatment of nausea and vomiting induced by cytotoxic chemotherapy and for the prevention and treatment of post-operative nausea and vomiting. Use in children: The use of dolasetron is contraindicated in paediatric patients Tropisetron Not currently listed on the WHO essential medicines list for children

FDA: Not approved TGA: For the treatment and prevention of post-operative nausea and vomiting in adults. Use in children: Since experience with tropisetron in children is still limited, its use cannot be recommended. Dexamethasone Currently listed on the WHO essential medicines list for children as an anti-allergic medication

FDA: Allergic disorder (adults, children); cerebral oedema (adults, children); collagen disease (adults, children); Cushing's syndrome

42 WHO EML – anti-emetics – October 2008

Drug International availability/ regulatory status (adults, children); disorder of ear (adults); disorder of endocrine system (adults, children); disorder of eye (adults, children); disorder of gastrointestinal tract (adults, children); disorder of hematopoietic structure (adults, children); disorder of respiratory system (adults, children); disorder of skin (adults, children); exacerbation of multiple sclerosis (adults, children); hypercalcemia of malignancy (adults, children); idiopathic thrombocytopenia pupura (adults); inflammatory disorder of musculoskeletal system (adults, children); Mycosis fungoides (adults, children); palliative management of leukaemia’s and lymphomas (adults, children); nephrotic syndrome (adults, children); Trichinosis (adults, children); tuberculosis of meninges (adults, children) TGA: Replacement therapy (adrenocortical insufficiency); disease therapy: collagen diseases, pulmonary disorders, blood disorders. rheumatic diseases, skin diseases, gastrointestinal disorders, oedema, eye disorders, neoplastic states, endocrine disorders. Preoperative and postoperative support Dexamethasone may be used in any surgical procedure when the adrenocortical reserve is doubtful. This includes the treatment of shock due to excessive blood loss during surgery. Shock Dexamethasone may be used as an adjunct in the treatment of shock. Hyoscine Not currently listed on the WHO essential medicines list for children (transdermal) FDA: Motion sickness (adults); prophylaxis of postoperative nausea and vomiting (adults) TGA: Not approved Abbreviations: FDA, Food and Drug Administration (US); TGA, Therapeutic Goods Administration (TGA); World Health Organization. Source: DRUGDEX® evaluations (www.micromedex.com); MARTINDALE® database (www.micromedex.com); MIMS® Australia (http://www.mims.com.au); Gan et al (2007); WHO Model List of Essential Medicines for children (2007)

43