The AngCN Antiemetic Guidelines

The AngCN Antiemetic Guidelines Guidelines for the Management of Nausea and Vomiting in Adult Patients Receiving Chemotherapy and/or Radiotherapy AngCN Document Reference: AngCN-CCG-C31

CONTENTS 1.0 Introduction 1.1 Scope 1.2 Aims 1.3 Definitions 1.4 Grading of nausea and vomiting 2.0 Antiemetic Risk Assessment and Protocol 2.1 Emetogenic Risk of IV and Oral Chemotherapeutic Agents 2.2 Assessing the emetogenic potential of chemotherapy regimens 2.3 Risk assessment 2.4 Assessing patient risk factors 2.5 Antiemetic categories, approved agents and uses 2.6 Antiemetic regimen selection 2.7 Anticipatory nausea and vomiting 3.0 Management of Antiemetic Failure and Escalation Policy 3.1 Definition of antiemetic failure 3.2 Management of antiemetic failure 4.0 Radiation Induced Nausea and Vomiting 4.1 Principles of Management 4.2 Determinants of emetic risk 4.3 ChemoRadiation 4.4 Guidance 5.0 Adverse Drug Reactions Associated with Commonly used Antiemetics 6.0 Appendices 6.1 Action of antiemetics on main receptor sites 6.0 References 7.0 Acknowledgements

1.0 Introduction The following guidelines have been developed for use within the Anglia Cancer Network for adult oncology and haemato-oncology patients receiving chemotherapy and/or radiotherapy. 1.1 Scope The guidelines apply to the use of antiemetics within Trusts delivering appropriate chemotherapy drugs/regimens. GPs should not be requested to prescribe. 1.2 Aims 1.2.1 To reduce the risk of emesis and minimise the side effects and complications of antiemetic drugs. 1.2.2 To ensure appropriate prescribing and administration of antiemetics for patients receiving chemotherapy and/or radiotherapy, as approved through the Anglia Cancer Network Systemic Anti-cancer Therapies group. 1.3 Definitions Acute Nausea and Vomiting (N and V) N and V experienced during the first 24-hour period immediately after chemotherapy administration Delayed N and V N and V that occurs more than 24 hours after chemotherapy and may continue for up to 6 or 7 days after chemotherapy Anticipatory N and V N and V that occurs prior to the beginning of a new cycle of chemotherapy. It is either a learned response following chemotherapy induced N&V on a previous cycle or an anxiety response. It is most common after 3 to 4 cycles of chemotherapy with very badly controlled acute or delayed symptoms Breakthrough N and/or V Development of symptoms (nausea or vomiting), despite standard antiemetic therapy, which require treatment with an additional pharmacological agent Refractory N and V Patients who have failed on both standard and rescue medication

1.4 Grading of Nausea and Vomiting Grade Nausea Vomiting 5 Death Death 4 Life-threatening consequences Life-threatening consequences 3 Inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN indicated 24 hrs 6 episodes in 24 hrs; IV fluids, or TPN indicated 24 hrs 2 Oral intake decreased without significant weight loss, dehydration or malnutrition; IV fluids indicated <24 hrs 2 5 episodes in 24 h; IV fluids indicated <24 hrs 1 Loss of appetite without alteration in eating habits 1 episode in 24 hrs 1.4 Grading of Nausea and Vomiting...4 4.0 Radiation Induced Nausea and Vomiting...17 4.4 Guidance...18

2.0 Antiemetic Risk Assessment and Protocol 2.1 Emetogenic Risk of IV and Oral Chemotherapeutic Agents It should be noted that appropriate prophylaxis can prevent delayed nausea and vomiting, which is harder to treat. Antiemetic treatment should therefore be escalated rapidly to control nausea and vomiting. Antiemetic therapy needs to be tailored to the treatment regimen used, as these have varying emetogenic potential, and also to the individual patient to whom it is being given. Note: A chemotherapy regimen named in the table in section 2.5 does not imply approval to prescribe. It should be ensured that funding approval has been sought and approved before prescribing. 2.2 Assessing the Emetogenic Potential of Chemotherapy Regimens Level Risk Agent 5 Very High Cisplatin > 60mg/m2 4 High >90% Carmustine > 250 mg/ m 2 Cisplatin > 50mg/m 2 Cyclophosphamide > 1500mg/m 2 Dacarbazine Dactinomycin Epirubicin > 90mg/m 2 Ifosphamide 10 g/ m 2 Mechlorethamide Streptozocin Trabectedin Procarbazine oral 3 Moderate- High 31-90% 2 Low 10-30% 1 Minimal <10% Alemtuzumab Amsacrine Azacitidine Bendamustine Cabazitaxel Carboplatin Carmustine 250 mg/ m 2 Cisplatin 50mg/m 2 Clofarabine Cyclophosphamide 750-1500mg/m 2 Cytarabine >1g/m 2 Daunorubicin Doxorubicin > 60mg/m 2 Bortezomib Capecitabine Cetuximab Cyclophosphamide IV/PO < 750mg/m 2 Cytarabine < 1g/m 2 Docetaxel Doxorubicin < 60mg/m 2 Etoposide Everolimus Fludarabine Abiraterone Bevacizumab Bexarotene Bleomycin Busulfan (low dose) Chlorambucil Cladribine Dasatinib 5-Fluorouracil Gemcitabine Liposomal Doxorubicin Lapatinib Lenalidomide Mercaptopurine Methotrexate 50-250 mg/m 2 Mifamurtide Mitomycin C Mitoxantrone Erlotinib Gefitinib Hydroxyurea Ipilimumab Melphalan Mesna (IV) Methotrexate < 50mg/m 2 Nilotinib Epirubicin 90mg/m 2 Eribulin Imatinib Idarubicin Ifosphamide <10 g/ m 2 Irinotecan Melphalan (Single high dose) Methotrexate > 250 mg/m 2 Oxaliplatin Procarbazine oral Temozolomide Vinorelbine oral Paclitaxel Paclitaxel albumin Pemetrexed Pentostatin Rituximab Romidepsin Sunitinib Tegafur Teniposide Thalidomide Topotecan Trastuzumab Pazopanib Temsirolimus Vemurafenib Vinblastine Vincristine Vinorelbine Vinflunine Formatted: Italian (Italy) Formatted: English (U.K.) Formatted: Italian (Italy) Formatted: English (U.K.) Formatted: English (U.K.) Formatted: Italian (Italy) Formatted: Italian (Italy)

Note: Drug combinations have an additive emetic effect. If drugs from the same category are combined, the regimen is classified at a higher emetic risk. If drugs are from different categories, the emetic risk is according to the most emetic drug in the combination. 2.3 Risk Assessment Certain risk factors can be used to predict those patients likely to be more susceptible to the emetogenic effects of chemotherapy or radiotherapy: Female gender Young (<30 years old) History of nausea and vomiting (e.g. sickness in pregnancy, motion sickness) Poor control of emesis with prior chemotherapy or radiotherapy Anxiety 2.4 Assessing Patient Risk Factors Risk Factor Action Chemotherapy induced nausea and vomiting (CINV) after previous chemotherapy If level < 4 add one to level Female gender Young age< 30 Drink Little or no Alcohol If level 3 or more then add one to level Anxiety History of Motion Sickness High level of anxiety prior to chemotherapy Add Lorazepam 1mg or Levomepromazine 6-12.5mg P.O. 1 hour before chemotherapy NB Excess alcohol intake reduces emetic risk: Women >14units/week, Men >21units/wk Other Potential Risk Factors: - Partial or complete bowel obstruction - Brain metastases - Electrolyte imbalance (hypercalcaemia, hyperglycaemia, hyponatraemia and uraemia) - Opiod induced nausea and vomitting

2.5 Antiemetic Categories, Approved Agents and Uses Many chemotherapy regimens for haemato-oncology patients incorporate corticosteroid treatment (commonly with prednisolone or dexamethasone). These patients should NOT receive dexamethasone as part of their antiemetic regimen even if the chemotherapy regimen falls into Category 2, 3 or 4 in section 2.2 (the Emetogenic Risk table). Generally no patient with acute leukaemia should receive dexamethasone as an antiemetic even if the drug/regimen falls into category 2, 3 or 4 (although some of these regimens may include a corticosteroid as part of the anti-cancer treatment). Drug / Regimen Tumour Site Antiemetic level Comments or special instructions A ABCM Haemato-onc 3 AB week only ABCM Haemato-onc 1 CM week only Abiraterone Urology (prostate) 1 ABVD Haemato-onc 4 AC Breast 3 ACE Germ cell 4 ADE (AML 15) Haemato-onc 3 No dexamethasone as antiemetic Alemtuzumab Haemato-onc 3 Amsacrine Haemato-onc 3 Asparaginase Haemato-onc 1 Azacitidine Haemato-onc 3 B BCG intravesical Urology 1 Bendamustine Haemato-onc 3 BEP Germ cell 5 Including 3-day and 5-day Bevacizumab Lower GI 1 In combination with fluoropyrimidine based chemotherapy Bexarotene Skin (cutaneous T 1 cell lymphoma) Bleomycin Various 1 Dexamethasone 8mg PO premedication to prevent reactions Bortezomib Haemato-onc 2 Busulfan (low dose) Haemato-onc 1 C Cabazitaxel Urology (prostate) 3 No dexamethasone TTO as antiemetic as regimen includes prednisolone CAP Lung (thymoma) 4 Capecitabine Lower GI 1 Capecitabine / Various 4 Cisplatin Capecitabine / Lower GI / Upper 2 Irinotecan GI Capecitabine / Breast 1 Lapatinib Carboplatin Germ cell / Gynaecology / Breast Carboplatin / Breast 3 3 Includes high dose e.g. AUC7 & AUC10

Docetaxel Carboplatin / Lung / Etoposide Neuroendocrine Carboplatin / 5-FU Head & neck / Upper GI Carboplatin (weekly with RT) Carmustine Haemato-onc / 3 3 Head & neck 4 Omit post-chemotherapy dexamethasone 3 ( 250mg/m 2 ) CNS 4 (>250mg/m 2 ) CAV Lung 3 CDT Haemato-onc 1 Cetuximab Lower GI 2 Cetuximab / Irinotecan / Capecitabine Lower GI 2 Cetuximab / Lower GI 2 Irinotecan / 5FU Cetuximab / Lower GI 3 Oxaliplatin / 5FU Chlorambucil Haemato-onc 1 ChlVPP Haemato-onc 1 CHOP Haemato-onc 4 No dexamethasone as antiemetic CIA Gynaecology 4 Cisplatin Dose > Various 5 60mg/m 2 Cisplatin 60mg/m 2 Various 4 Cisplatin (weekly with RT) Cisplatin / Docetaxel / 5FU Cisplatin / Gynaecology / Doxorubicin Head & Neck Cisplatin / Etoposide Gyanecology / Lung / Neuroendocrine Head & Neck / 3 Omit post-chemotherapy Gynaecology dexamethasone Head & Neck 5 Cisplatin weekly / Gynaecology 4 oral etoposide Cisplatin / 5-FU Various 5 All regimens Cisplatin / Gynaecology 3 Topotecan Cladribine Haemato-onc 1 Clofarabine Haemato-onc 3 CMD Haemato-onc 2 No dexamethasone as antiemetic CMF Breast 2 CMV Urology (bladder) 5 C-VAMP Haemato-onc 3 No dexamethasone as antiemetic CVD Neuroendocrine 4 CVP Haemato-onc 3 No dexamethasone as antiemetic Cyclophosphamide - Oral only Cyclophosphamide - IV doses <1500mg/m 2 Cyclophosphamide - IV doses >1500mg/m 2 Various 1 Various 3 Haemato-onc 4 4 5

Cyclophosphamide / Breast 3 Docetaxel Cytarabine - IV doses <1000mg/m2 Haemato-onc 2 No dexamethasone as antiemetic if AML Cytarabine - IV doses 1000mg/m 2 Haemato-onc 3 No dexamethasone as antiemetic if AML C-Z-DEX Haemato-onc 3 No dexamethasone as antiemetic D DA (AML 15/16) Haemato-onc 3 No dexamethasone as antiemetic Dacarbazine Melanoma 4 Dactinomycin Gestational 4 trophoblastic tumours Dasatinib Haemato-onc 1 Daunorubicin / Haemato-onc 3 No dexamethasone as antiemetic Clofarabine (AML 16) Daunorubicin Haemato-onc 3 De Gramont Lower GI 1 (standard/modified) Docetaxel Breast / Upper GI 2 Dexamethasone 8mg PO BD for 3 days starting day before docetaxel + post chemo domperidone Docetaxel Urology (prostate) 2 Given the concurrent use of prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel + domperidone Docetaxel / Capecitabine Breast 2 Dexamethasone 8mg PO BD for 3 days starting day before docetaxel Docetaxel / Carboplatin Lung / Gynaecology + domperidone 3 Dexamethasone 8mg PO BD for 3 days starting day before docetaxel + ondansetron / domperidone Docetaxel / Cisplatin Lung 4 Dexamethasone 8mg PO BD for 3 days starting day before docetaxel + ondansetron / domperidone Docetaxel / Gemcitabine Sarcoma / Gynaecology Docetaxel / Upper GI 3 Irinotecan Doxorubicin Various 3 Doxorubicin weekly Breast 2 E EC Breast 3 ECarboF Upper GI/Unknown Primary ECarboX Upper GI/ 4 Unknown Primary ECE Lung (thymoma) 4 ECF Upper GI/Unknown Primary 4 2 Dexamethasone 8mg PO BD for 3 days starting day before docetaxel + post chemo domperidone 3

ECX Upper GI/ 4 Unknown Primary EDP + Mitotane Neuroendocrine 3 EMA-CO Gestational 4 EMA weeks only Trophoblastic Tumour EMA-CO Gestational 2 CO weeks only Trophoblastic Tumour EOF Upper GI 3 EOX Upper GI 3 EP Germ cell / lung 4 Epi-CMF Breast 3 Epirubicin only Epi-CMF Breast 2 CMF only Epirubicin Breast 3 Epirubicin / Gynaecology 3 Carboplatin Epirubicin (weekly) Breast 2 Eribulin Breast 3 Erlotinib Lung 1 ESHAP Haemato-onc 4 No dexamethasone as antiemetic Etoposide - Oral Various 1 only Etoposide - IV only Various 2 (except high dose etoposide for germ cell) Etoposide Germ cell 3 High dose 1.6g/m 2 etoposide EV Lung 2 Everolimus Renal 1 F FAD Haemato-onc 3 No dexamethasone as antiemetic FC (Fludarabine / Haemato-onc 3 Cyclophosphamide) FEC - All epirubicin Breast 3 doses up to 75mg/m2 FEC 100 Breast 4 FEC-T Breast 4 FLAG-Ida (AML 15) Haemato-onc 3 No dexamethasone as antiemetic Fludarabine - Oral Haemato-onc 1 and IV 5-Fluorouracil Various 1 Includes continuous infusional 5- FU, weekly bolus, and 5-FU + RT regimens FMD Haemato-onc 2 No dexamethasone as antiemetic G GCP Germ cell 3 Dexamethasone 20mg IV pre 3 weekly paclitaxel (instead of 8mg) plus other antiemetics Gefitinib Lung 1 Gemcitabine Various 2 Gemcitabine / Lung / Breast / 3 Carboplatin Gyanecology Gemcitabine / Cisplatin Various 4

Gemcitabine / Breast / Bladder / 2 Paclitaxel Germ Cell Gem-TIP Germ Cell 4 Dexamethasone 20mg IV pre 3 weekly paclitaxel (instead of 8mg) plus other antiemetics Gemtuzumab Haemato-onc 1 Ozogamicin (Mylotarg ) H Hydroxycarbamide Haemato-onc 1 (Hydorxyurea) Hyper-CVAD + Haemato-onc 3 No dexamethasone as antiemetic Rituxumab I Idarubicin Haemato-onc 3 No dexamethasone as antiemetic if AML Ifosfamide Various 3 Ifosfamide / Sarcoma 3 Doxorubicin Imatinib GIST / Haematoonc 1 Interferon alfa Renal 1 Ipilimumab Melanoma 1 IPO Germ Cell 3 Irinotecan Lower GI 3 Irinotecan / 5FU (FOLFIRI) Lower GI 3 Includes De Gramont & weekly bolus 5FU Irinotecan/mitomycin Upper GI 3 C Irinotecan (weekly) Lower GI 2 IVE Haemato-onc 3 L Lapatinib Breast 1 Lenalidomide Haemato-onc 1 Liposomal Gynaecology 2 Doxorubicin Liposomal Gynaecology 3 Doxorubicin / Carboplatin Lomustine CNS 1 M MACE (AML 15) Haemato-onc 2 No dexamethasone as antiemetic Melphalan Haemato-onc 1 Including PO melphalan + prednisolone; IV melphalan + dexamethasone. Mercaptopurine Haemato-onc 1 No dexamethasone as antiemetic if ALL Methotrexate - oral Various 1 and IV doses <300mg/m 2 only. Methotrexate - IV doses > 300mg/m 2 Haemato-onc 3 No dexamethasone as antiemetic if ALL MidAC (AML 15) Haemato-onc 3 No dexamethasone as antiemetic Mifamurtide Sarcoma 3 MiniBEAM Haemato-onc 3 Day 1 & 6 only MiniBEAM Haemato-onc 2 Day 2 5 only

Mitomycin C - Urology 1 Intravesical only Mitomycin C / Lower GI 2 For Mitomycin C weeks only Capecitabine Mitomycin C/ 5-FU Lower GI 2 All regimens. For Mitomycin C weeks only. Mitoxantrone Various 2 MM Breast 2 MMM Breast 2 MVAC Urology (bladder) 5 MVC Urology 4 MVP Mesothelioma 4 N Nilotinib Haemato-onc 1 O OMB Germ cell 3 Oxaliplatin Lower GI 3 Oxaliplatin / Lower GI 3 Capecitabine (XELOX) Oxaliplatin / 5FU Lower GI 3 Includes De Gramont & weekly bolus 5FU. P Paclitaxel Various 2 Dexamethasone 20mg IV pre three weekly paclitaxel or 8mg IV pre weekly paclitaxel plus other antiemetics Paclitaxel albumin Breast 2 (Abraxane ) Paclitaxel / Carboplatin Gynaecology / Lung 3 Dexamethasone 20mg IV pre three weekly paclitaxel or 8mg IV pre weekly paclitaxel plus other antiemetics Paclitaxel / Cisplatin Urology (bladder) Pazopanib Renal / Hepatobiliary 1 PCV CNS 1 Pemetrexed / Lung / Carboplatin Mesothelioma Pemetrexed / Cisplatin Lung / Mesothelioma 2 Dexamethasone 4mg PO BD for 3 days starting day before pemetrexed + other antiemetics 4 Dexamethasone 4mg PO BD for 3 days starting day before pemetrexed + other antiemetics Pentostatin Haemato-onc 1 (Deoxycoformycin) PMB Gynaecology 4 PMitCEBO Haemato-onc 3 MitCE week only. No dexamethasone as antiemetic. PMitCEBO Haemato-onc 1 BO week only POMB Germ cell 4 Procarbazine Haemato-onc 4 R Raltitrexed Lower GI 2 R-CHOP Haemato-onc 3 No dexamethasone as antiemetic R-CVP Haemato-onc 3 No dexamethasone as antiemetic R-ESHAP Haemato-onc 4 No dexamethasone as antiemetic

R-FC Haemato-onc 3 Rituximab Haemato-onc 1 R-IVE Haemato-onc 3 R-MiniBEAM Haemato-onc 3 Day 1 & 6 only R-MiniBEAM Haemato-onc 2 Day 2 5 only Romidepsin Haemato-onc 3 R-PMitCEBO Haemato-onc 3 MitCE week only. No dexamethasone as antiemetic. R-PMitCEBO Haemato-onc 1 BO week only S Sorafenib Renal / 1 Hepatobiliary Stanford V Haemato-onc 3 Week 1, 3, 5, 7, 9, 11 only. No dexamethasone as antiemetic. Stanford V Haemato-onc 1 Week 2, 4, 6, 8, 10, 12 only Streptozocin / Neuroendocrine 4 Capecitabine Streptozocin / 5FU Neuroendocrine 4 Sunitinib Renal / GIST 1 T Tegafur Lower GI 1 Temozolamide CNS 1 Temsirolimus Renal 1 Thalidomide Haemato-onc 1 Thioguanine Haemato-onc 1 TIP Germ cell 5 Dexamethasone 20mg IV pre 3 weekly paclitaxel (instead of 8mg) plus other antiemetics as per section Topotecan (IV) Gynaecology 2 Topotecan (oral) Lung 2 Trabectedin Sarcoma 4 Trabectedin / Gynaecology 4 Liposomal Doxorubicin Trastuzumab Breast 1 Trastuzumab / Upper GI 5 Cisplatin / Capecitabine Trastuzumab / Upper GI 5 Cisplatin / 5FU Trastuzumab/ Docetaxel Trastuzumab/ Paclitaxel Trastuzumab/ Vinorelbine U UK ALL XI Induction Phase 1 UK ALL XI Induction Phase 2, Day 1, 15, 29 Breast 2 Dexamethasone 8mg PO BD for 3 days starting day before docetaxel + metoclopramide as per section Breast 2 Dexamethasone 20mg IV pre 3 weekly paclitaxel (instead of 8mg) plus other antiemetics as per section Breast 1 Haemato-onc 3 No dexamethasone as antiemetic Haemato-onc 3 No dexamethasone as antiemetic

UK ALL XI Induction Haemato-onc 2 No dexamethasone as antiemetic Phase 2 Day 8, 22 UK ALL XI Haemato-onc 3 No dexamethasone as antiemetic Intensification high dose MTX UK ALL XI Haemato-onc 2 No dexamethasone as antiemetic Consolidation Cycle 1, 2, 4 UK ALL XI Haemato-onc 3 No dexamethasone as antiemetic Consolidation Cycle 3 Day 1, 8, 15, 22, 29 V VAD Haemato-onc 3 No dexamethasone as antiemetic VAMP Haemato-onc 3 No dexamethasone as antiemetic VAPEC-B - Week 1 Haemato-onc 3 No dexamethasone as antiemetic & 3 only. VAPEC-B Week 2 & Haemato-onc 1 No dexamethasone as antiemetic 4 only VeIP Urology 3 Vemurafenib Melanoma 1 Vinblastine Various 1 Vincristine Various 1 Vinflunine Urology (bladder) 1 Vinorelbine Breast / lung 1 Includes IV/PO vinorelbine Vinorelbine/ Lung 3 Includes IV/PO vinorelbine Carboplatin Vinorelbine/ Lung 4 Includes IV/PO vinorelbine Cisplatin VIP Germ cell 5 Z Z-DEX Haemato-onc 3 No dexamethasone as antiemetic

2.6 Antiemetic Regimen Selection The appropriate antiemetic regimen for the Regimen category designated in the table in section 2.5 should be selected as follows: Level Risk Pre-Chemotherapy Post-Chemotherapy 1 <10% No prophylaxis needed Observation or domperidone or metoclopramide 10-20mg QDS PRN 2 Low 10-30% 3 Mod-high 31-90% 4 High >91% IV dexamethasone 8mg ondansetron 8mg IV plus dexamethasone 8mg IV ondansetron 8 mg IV plus dexamethasone 8mg IV Domperidone or metoclopramide 10mg- 20mg QDS days 1-5 PRN Oral dexamethasone 4 mg BD 2-3 days +/- Oral ondansetron 8mg BD for 2 days plus domperidone or metoclopramide 10-20mg QDS prn Oral dexamethasone 4 mg BD 3-4 days plus Oral ondansetron 8mg BD for 3-4 days plus domperidone or metoclopramide 10-20mg QDS prn NB: If a patient does not have an adequate response to the above regimens then the dose of ondansetron may be escalated to 16mg per dose or aprepitant should be considered according to Trust policy/availability. Where patients meet the following clinical criteria then palonosetron may be substituted for ondansetron: Dysphagia Diabetes (where dexamethasone contraindicated). 5 Highly Aprepitant 125mg PO Emetic or (plus level 4 antiemetics) Grade 3-4 CTC N and V 80mg od for 2 days after chemotherapy (plus level 4 antiemetics) 2.7 Anticipatory nausea and vomiting Prescribe lorazepam 1-2mg orally/sublingually at least 1 hour prior to chemotherapy, in addition to standard antiemetics. If severe, consider 1mg night before chemotherapy and 1mg on the morning of chemotherapy.

3.0 Management of Antiemetic Failure and Escalation Policy 3.1 Definition of Antiemetic Failure Antiemetic failure is defined as two or more episodes of vomiting or prolonged/distressing nausea occurring within 24 hours after chemotherapy treatment despite being treated with antiemetics. All patients should be asked about their response to previous antiemetic treatment, where appropriate, and prior antiemetic failure before each course of chemotherapy. Clinicians should ensure that the patient has taken post chemotherapy drugs regularly as prescribed. There are three significant categories: Acute nausea and vomiting which occurs within 24 hours of chemotherapy. Occurs with most cytotoxic agents to some extent. Delayed nausea and vomiting which occurs later than 24 hours after chemotherapy. Cisplatin, carboplatin, cyclophosphamide and the anthracyclines are known to cause delayed emesis. Anticipatory nausea and vomiting which occurs days or hours before chemotherapy. 3.2 Management of Antiemetic Failure If there is no nausea or vomiting, continue on existing anti-emetic regimen. If breakthrough treatment is required, give an additional agent that is from a different drug class prn, e.g.: Prochlorperazine 5-10mg po every 4 to 6 hours or 3-6mg buccally b.d. OR Metoclopramide 10-40mg po/iv every 4 to 6 hours OR Lorazepam 0.5-2mg po/iv/sublingual every 4 to 6 hours OR Levomepromazine 6.25mg 12.5mg od - tds po/sc (12.5mg po = 6.25mg sc) OR Haloperidol 1-2 mg po every 4 to 6 hours OR Nabilone 1-2 mg po bd OR dexamethasone if not previously given (or extend the course if delayed nausea and vomiting) Consider adding lorazepam before and after chemotherapy for anti-emetic failure within the first 24 hours and for longer if nausea persists once ondansetron course has finished. Do not extend the length of treatment of ondansetron. If nausea and vomiting is controlled with breakthrough anti-emetic regimen, then continue the breakthrough medication on a regular basis. If nausea and vomiting not controlled with breakthrough medication, move up to a higher level prophylactic anti-emetic regimen. Dexamethasone is the most useful agent for delayed nausea and vomiting. Dexamethasone schedule for delayed phase can be administered on a reducing dose e.g. 4mg bd for 1 day, 4mg od for 1 day 2mg od for 2 days to minimise dexamethasone side effects. Lorazepam causes amnesia and sedation, and is best for anxious patients or for anticipatory nausea and vomiting. To ensure absorption in vomiting patients, consider route of administration of antiemetics e.g. subcutaneous, intravenous, rectal, buccal, sublingual (Do NOT use suppositories in neutropenic patients) Ensure anti-emetics cover the full period of nausea and vomiting. Consider addition of antacids or proton pump inhibitors for patients sensitive to dexamethasone. Patients should be told to contact the ward if they start vomiting at home. Delayed vomiting may cause acute renal failure due to dehydration exacerbating the nephrotoxicity of chemotherapy.

If the patient has failed a level 4 regimen then the following options should be explored: Level Option Pre-Chemotherapy Post-Chemotherapy 4a Maintain dose of Ondansetron and add additional agents Ondansetron 8 mg IV plus Dexamethasone 8mg IV Oral dexamethasone 4 mg BD on days 1 to 4 plus Oral Ondansetron 8mg BD for 4 days post chemo. Plus 4b 4c Escalate dose of Ondansetron Replace Ondansetron with Palonosetron Ondansetron 12 mg IV plus Dexamethasone 8mg IV Replace I.V and oral Ondansetron with Palonosetron I.V. 250 micrograms 4d Add aprepitant 125mg PO prior to chemotherapy 80mg od for 2 days after chemotherapy 4.0 Radiation Induced Nausea and Vomiting 4.1 Principles of Management As for chemotherapy-induced nausea and vomiting, the goal of antiemetic therapy is to prevent nausea and vomiting. The risk of radiation induced emesis varies with the treatment administered. 4.2 Determinants of Emetic Risk The determinants of emetic risk in relation to radiotherapy are as follows: The actual treatment field The dose of radiotherapy administered per fraction The pattern of fractionation 4.3 ChemoRadiation For patients receiving chemoradiation schedules, treat with antiemetic therapy according to the highest emetogenic risk based on the chemotherapy regimen or the radiotherapy treatment field.

4.4 Guidance Risk Level Irradiated Area Minimal Extremities Low Breast Head and neck Cranium Lower thorax region Pelvis Pre-radiotherapy Rescue with domperidone or ondansetron Prophylactic or rescue ondansetron Prophylactic Prophylactic antiemetics should continue throughout radiation treatment if patient experiences RINV while receiving therapy For patients who experience RINV while receiving rescue therapy only, prophylactic treatment should continue until radiotherapy is complete Patients should receive antiemetic prophylaxis according to the emetogenicity of concurrent chemotherapy, unless the emetic Cranospinal Moderate Upper abdomen Hemibody irradiation Upper abdomen, abdominalpelvic, mantle, craniospinal irradiation, and cranial radiosurgery Ondasetron (before each fraction for the entire course of radiotherapy) +/- a short course of dexamethasone during fractions 1 to 5 risk with the planned radiotherapy is higher High Total body irradiation (TBI) Total nodal irradiation Ondansteron (before each fraction and for at least 24 hours after completion of radiotherapy) Plus 5 day course of dexamethasone during fractions 1 to 5.

5.0 Adverse Drug Reactions associated with commonly-used Antiemetics 5.1 5HT 3 receptor antagonists cause constipation and headache, which can exacerbate nausea. Patients need to be advised accordingly, e.g. lactulose to relieve constipation and paracetamol to relieve headache. If constipation is a problem then alternative treatment options are cyclizine 50mg three times a day or domperidone 20mg four times a day. Laxatives may also be prescribed fluid intake should be encouraged if possible. 5.2 Metoclopramide can rarely cause agitation or the development of extra-pyramidal symptoms particularly in the young female patients. These can occur up to 24 hours after a dose and may vary from facial grimacing and dystonic movements to odd feelings in the mouth, restlessness, somnolence and irritability. Bowel transit time may be reduced and some patients experience diarrhoea. 5.3 Domperidone and metoclopromide should not be used when stimulation of the gastric motility could be harmful. Avoid in gastro-intestinal haemorrhage, mechanical obstruction or perforation. 5.4 Levomepromazine inhibits cytochrome P-450. Common side effects are somnolence, asthenia, dry mouth, hypotension, photosensitivity and skin reactions. Avoid in patients with liver dysfunction. 5.5 Lorazepam can cause drowsiness and may affect performance of skilled tasks (driving) 5.6 Prochlorperazine may cause drownsiness. A mild leukopenia occurs in up to 30% of patients on prolonged high dosage. Avoid in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostatic hypertrophy. 5.7 Dexamethasone can cause sleep disturbances, hyperactivity and excessive appetite. They also impaired glucose tolerance. Patients may experience perineal discomfort if the drug is given by I/V bolus. This can be avoided by administration via IV infusion. Use with care in patients with diabetes mellitus. 5.8 Cyclizine may cause antimuscarinic side effects such as dryness of the mouth and drowsiness. Children and the elderly are more susceptible to these effects. 5.9 Aprepitant common ADRs include headaches, hiccups and fatigue. When given in combinations with corticosteroids, the SPC suggests that the oral dexamethasone dose is reduced by 50%, methylprednisolone IV dose is reduced by 25% and the oral dose by 50%. NB for practical reasons it is not necessary to halve post chemotherapy dexamethasone doses as per the aprepitant trial data.

6.0 Appendices 6.1 Action of Antiemetics on Main Receptor Sites Drug D 2 antagonist H 1 antagonist Muscarinic antagonist 5HT 2 antagonist 5HT 3 antagonist 5HT 4 agonist NK1 inhibitor CB ago Metoclopramide ++ 0 0 0 + ++ 0 0 Domperidone ++ 0 0 0 0 0 0 0 Cyclizine 0 ++ ++ 0 0 0 0 0 Hyoscine 0 0 +++ 0 0 0 0 0 Haloperidol +++ 0 0 0 0 0 0 0 Levomepromazine ++ +++ ++ +++ 0 0 0 0 Aprepitant 0 0 0 0 0 0 +++ 0 Ondansetron 0 0 0 0 +++ 0 0 0 Granisetron 0 0 0 0 +++ 0 0 0 Lorazepam 0 0 0 0 0 0 0 0 Nabilone 0 0 0 0 0 0 0 ++ Prochlorperazine +++ ++ + +/++ 0 0 0 0 Pharmacological activity 0=none or insignificant, + = slight, ++ = moderate, +++ = marked Table adapted from Twycross R, Wilcock A, - Palliative Care Formulary Forth Edition (2011)

7.0 References 1. Jordan, K. et al. Oncologist 2007;12:1143-1150 2. Hesketh P.J Chemotherapy Induced Nausea and Vomiting (Review Article) N England Journal Med 2008; 358: 2482-94 3. Hesketh et al. Proposal for Classifying the Acute Emetogenicity of Cancer Chemotherapy. J Clin Oncology 1997 15(1):103-9 4. Guideline update for MASCC and ESMO in the prevention of chemotherapy and tradiotherapy induced nausea and vomiting : results of the Perugia consensus conference Annals of Oncology 2010: 21(supplement 5) v 232-v243 5. Aapro et al. A phase III double blind, randomised trial of Palonosetron compared with ondansetron in preventing chemotherapy induced nausea and vomiting following highly emetogenic chemotherapy Annals of Oncology 2006 17:1441-9 6. Husband A, Worsley A, Nausea and Vomiting pharmacological management Hospital Pharmacist 2007; 14:189-191 7. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 4.0. Bethesda, Md: National Cancer Institute, Division of Cancer Treatment and Diagnosis, 2009. 8. Navari R M. Pharmacological management of chemotherapy-induced nausea and vomiting. Focus on recent developments. Drugs 2009; 69 (5): 515-533 9. National Comprehensive Cancer Network: Antiemesis. NCCN Clinical Practice Guidelines in Oncology v.1.2011. Available at www.nccn.org. Accessed 29 October 2012 10. Basch et al ASCO guidelines Antiemetics : American Society of Clinical Oncology Clinical Practice Guideline Update 2011 8.0 Acknowledgements 8.1 King s Lynn Antiemetic Guideline 8.2 Mount Vernon Antiemetic Guideline 8.3 Surrey, West Sussex and Hampshire Cancer Network. Guidelines for the Use of Antiemetics with Chemotherapy. June 2009. Accessed via swshcn.nhs.uk. 8.4 Thames Valley Cancer Network. Antiemetic guidelines for the prophylaxis of Chemotherapy and Radiotherapy induced nausea and vomiting in adults (for use by Haematologists and Oncologists). September 2011. Accessed via tvcn.nhs.uk. 8.5 Debbie Morrison Cambridgeshire PCT - Author of the initial working draft of this Guideline