Antiemetics in chemotherapy

Transcription

1 Antiemetics in chemotherapy Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact Name and Job Title (author) Directorate & Speciality Date of submission Date on which guideline must be reviewed (this should be one to three years) Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Abstract Key Words Guideline for the prevention and management of nausea and vomiting in children and young people receiving chemotherapy Beverly Harwood, Paediatric Oncology Pharmacist, Katie Rogers, Clinical Educator, Ghazala Javid, Paediatric Oncology Pharmacist, Leicester Royal Infirmary Dani Jones, Clinical Educator Jenni Hatton, Paediatric Oncology Network Pharmacist Family Health, Paediatric Haematology/Oncology May 2015 May 2018 This guideline applies to all children and young people under the age of 19 years. This guideline describes the principles and management of nausea and vomiting in children and young adults receiving chemotherapy. antiemetic nausea vomiting chemotherapy; paediatrics; children 1a Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? meta analysis of randomised controlled trials 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasi-experimental study 3 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the clinical experience of the guideline developer Consultation Process Target audience See references All paediatric oncology and haematology consultants, lead nurses, pharmacists and CYPICs Educator All clinical staff working in paediatric oncology to include doctors, nurses and pharmacists. This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Jenni Hatton Page 1 of 12 Version 5 May 2015

2 Document Control Issue Status Version Issue Date Lead Author V1 V2 Aug 2010 Beverly Harwood Paediatric Oncology Pharmacist V3 Aug 2013 Adam Henderson Paediatric Oncology Pharmacists. V4 Sept 2013 Beverly Harwood Paediatric Oncology Pharmacist V5 May 2015 Jenni Hatton Paediatric Oncology Pharmacist Dani Jones Clinical Educator for Children & Young People CYPICS Description Reviewed. Few changes Addition information regarding EMA warning about metoclopramide Amended first and second line treatments to comply with MHRA guidance on metoclopramide General Notes; This guideline is part of the CYPICS* documentation from *Children s and Young Peoples Integrated Cancer Service I can confirm that this guideline was reviewed by the members of the EMCYPICS team and, as its aim is for use by members of that team only, it has not received full circulation to all members of the Children s Hospital. Martin Hewitt Guideline Lead 22 June 2015 Jenni Hatton Page 2 of 12 Version 5 May 2015

3 Introduction Nausea and vomiting are two of the most distressing side effects of chemotherapy. Vomiting, in particular is a major concern for children and young people as this group are at particular risk of electrolyte imbalance, dehydration and weight loss. Not only do these factors place them at increased risk for future treatments but the emotional and physical distress caused to children, young people, and parents has a negative impact on their quality of life. It is therefore imperative that health professionals working with children and young people with cancer are able to provide suitable and effective antiemetic therapy. Emesis is a complex process that is mediated by both the central and peripheral nervous systems in response to several neurotransmitters including serotonin, dopamine, histamine, acetylcholine and neurokinin-1. Chemotherapy-induced nausea and vomiting is classified as anticipatory, acute and delayed. Anticipatory nausea and vomiting generally occurs before treatment commences and is triggered by taste, odour, sight, anxiety or if previous antiemetic control has been poor. Acute nausea and vomiting occurs up to 24 hours after treatment and delayed nausea and vomiting occurs from 24 hours to several days after treatment. Standard antiemetic regimes in Figure 2 may need adapting if anticipatory and/or delayed nausea and vomiting are experienced (see Figure 3 and 4). Principles Aim to minimise nausea and vomiting by administering anti-emetics regularly. For children who have not had chemotherapy before, first line antiemetic therapy should be selected based on the most emetogenic drug being given (see Figure 2). All children should receive antiemetic therapy according to the emetogenicity of the chemotherapy they are to receive and their previous experience of chemotherapy (see Figure 1). Always aim to use the oral route first if it is suitable. Consider starting antiemetics 24 hours prior to commencement of chemotherapy if child/young person has experienced chemotherapy-induced nausea and vomiting previously. Most children receive combination treatment with more than one drug, so the anti-emetic prescription should be based on the drug with highest emetogenic potential. However if two or more moderately emetogenic drugs are prescribed together then the emetogenicity of the course is increased and patients should be treated as if receiving highly emetogenic chemotherapy. Jenni Hatton Page 3 of 12 Version 5 May 2015

4 Figure 1: Antiemetic treatment choice Has the patient had prescribed chemotherapy agents previously? Yes No Was their antiemetic treatment successful?* Identify most emetogenic chemotherapy agent Yes No Prescribe regular antiemetics as per previous admission Prescribe regular antiemetics as per Figure 3 Prescribe regular antiemetics as per Figure 2 Has patient vomited and/or retched more than twice in 24 hours or experienced more than 4 hours of nausea? Yes No Add/change antiemetics as per Figure 4 Continue current antiemetics for this and subsequent admissions *Treatment is unsuccessful if child has vomited and/or retched more than twice in 24 hours or if they experienced more than 4 hours of nausea during chemotherapy Jenni Hatton Page 4 of 12 Version 5 May 2015

5 Figure 2a: First line antiemetic therapies Emetogenicity Chemotherapy Agent Recommended initial anti-emetic Low Asparaginase None Bevacizumab Fludarabine Mercaptopurine Methotrexate <50mg/m 2 Rituximab Vinblastine Vincristine Vinorelbine Moderate Bleomycin Ondansetron Oral / IV Cytarabine <100mg/m 2 <0.6m 2 1-2mg three times a day Etoposide m 2 4mg three times a day Gemcitabine >1.2m 2 8mg three times a day Methotrexate <5g/m 2 Topotecan N.B. If 2 moderately emetogenic drugs given together treat as per highly emetogenic chemotherapy. Start 30 to 60 minutes before chemo, repeat every 8-12 hours during chemotherapy and for at least 24 hours post chemo. High Very High Actinomycin Busulphan Cyclophosphamide <1000mg/m 2 Cytarabine mg/m 2 Daunorubicin Doxorubicin Epirubicin Idarubicin Irinotecan Methotrexate >5g/m 2 Procarbazine Temozolomide Carboplatin Carmustine Cisplatin Cyclophosphamide >1000mg/m 2 Cytarabine >500mg/m 2 Dacarbazine Ifosfamide Lomustine Under 12 years Ondansetron as above AND Domperidone Oral 1 month - 12yrs AND <35kg 250 microgram/kg three times a day > 12yrs or >35kg 10mg three times a day (max 30mg/day) 12 years and over Ondansetron as above AND Aprepitant oral >12 yrs AND >40kg 125mg once on day 1, one hour before the start of chemotherapy, then 80mg once daily on day 2 and day 3 of cycle. N.B if nausea & vomiting continues or oral route is not tolerated swap to; Metoclopramide IV for > 1 year old 0.15mg/kg three times a day (max 30mg / day) N.B. Contraindicated in <1yr old. Maximum 5 day duration (EMA recommendation August 2013). If <1yr use second line alternative. Under 12 years 12 years and over Ondansetron AND Metoclopramide Oral (first line) or IV (doses as above) +/- Ondansetron AND Aprepitant (as above) +/- Dexamethasone Oral / IV 2.5mg/m 2-5mg/m 2 twice to three times a day Round to nearest 0.5mg (max daily dose 10mg/m 2 ) N.B. Only to be used for a max total of 5 days. Discuss with consultant for patients with osteosarcoma or brain tumours. Do NOT use in patients receiving steroids as part of their chemotherapy. Jenni Hatton Page 5 of 12 Version 5 May 2015

6 Figure 2b: First line antiemetic therapies Drug and Preparation Ondansetron Tablets 4mg, 8mg Oral solution SF 4mg/5ml Ondansetron melt 4mg, 8mg Injection 2mg/ml Mechanism of action 5-HT 3 serotonin antagonist. Acts at the CTZ and in the GI tract. Side effects and comments Side effects: Headaches, constipation, flushing and occasional diarrhoea. Reduce dose in moderate / severe hepatic impairment. Less effective against delayed nausea and vomiting. Use metoclopramide / domperidone instead. Domperidone Tablet 10mg Suspension S/F 5mg/5ml Suppositories 30mg Aprepitant Capsules 120mg and 80mg Dexamethasone Tablets 500microgram and 2mg (can be dispersed) Oral solution S/F 2mg/5ml Injection 4mg/ml Metoclopramide Tablet 10mg Oral solution 5mg/5ml Injection 5mg/ml Antagonist of GI and central dopamine (D 2 ) receptors. Prokinetic properties. Use instead of metoclopramide for vomiting due to opioids or gastric stasis. Effective for delayed nausea and vomiting. Side effects: Rare extrapyramidal, rashes and rarely GI disturbances. Substance P Neurokinin receptor antagonist for prevention only; inhibits metabolism of dexamethasone reduce dose of dexamethasone by 50%. Prevents release of 5-HT 4 and 5-HT 3 in the GI. At low doses, Metoclopramide has dopamine antagonist (D 2 ) effect. At higher doses it has serotonin antagonist (5-HT 3, 5-HT 4 ) effect in the GI tract. PO 250micrograms/kg (max 20mg) TDS >12 years and >40kg 125mg orally once on day 1, then 80mg once daily on day 2 and day 3 of cycle. (max 7 days) Side effects: Insomnia, agitation, indigestion and mood and behaviour problems. Effective for delayed nausea and vomiting. Do NOT use in patients receiving steroids as part of their chemotherapy e.g. AML, ALL and BMT. Check with consultant for patients with osteosarcoma or brain tumours. It can help in delayed vomiting in children with CNS tumours who are receiving cisplatin (highly emetogenic) Side effects: Extrapyramidal (especially the young, < 10kg and girls) and sedation. Dystonic reactions more likely when daily dose exceeds 500 micrograms/kg. Contraindicated in < 1 year old and maximum 5 day duration due to concerns over side effects and efficacy (EMA recommendation August 2013) Procyclidine or benzatropine can be used to reverse its adverse effects. Can be useful in severe intractable vomiting due to radiotherapy and cytotoxics. Jenni Hatton Page 6 of 12 Version 5 May 2015

7 If a child vomits and/or retches more than twice in 24 hours, or has more than 4 hours of nausea add in further first line medication or change to/add a second line antiemetic (see Figure 4). If control is still unsatisfactory, discuss the addition of a further agent with senior medical staff and consider other possible causes of emesis (see Investigations). Anticipatory nausea and vomiting may be helped by the administration of lorazepam or other anxiolytic treatment hours before chemotherapy, particularly in adolescent patients. Non-drug therapies such as distraction, breathing techniques and muscle relaxation can also be helpful. Figure 3: Second line antiemetic choice (For extra information/doses see Figure 4) Is patient on maximal first line therapy? No Prescribe additional first line antiemetic (Fig. 2) Yes Does nausea/vomiting have anxiety component? Yes Consider lorazepam if > 12 years No Is nausea and vomiting controlled? No Consider other causes for nausea/vomiting and discuss following options with senior medical staff: 1. Add in domperidone if not already on. 2. Add levomepromazine in place of metoclopramide 3. Add cycllizine 4. Switch from ondansetron to granisetron (if stocked locally) 5. Other options to consider: a. Haloperidol (in place of levomepromazine and domperidone) b. Prochlorperazine c. Continuous granisetron infusion d. Nabilone e. Hyoscine Patches Ensure the anti-emetics for the following cycles are amended to reflect the successful treatment. Jenni Hatton Page 7 of 12 Version 5 May 2015

8 Figure 4: Second line antiemetic therapies Drug and Preparation Cyclizine Tablets 50mg (can be crushed) Injection 50mg/ml Granisetron Tablets 1mg Injection 1mg/ml Haloperidol Capsule 500microgram Scored Tablets 0.5mg, 1.5mg, 5mg,10mg, 20mg Oral liquid 1mg/ml, 2mg/ml and SP 1mg/5ml Injection 5mg/ml Levomepromazine Tablets 6mg (SP) and 25mg (can be halved or crushed) Injection 25mg/ml Indication, action, side effects and general comments. Antihistamine (H 1 receptor) with antimuscarinic properties. No evidence for use in chemotherapy induced nausea and vomiting, but has been used in other centres. Cyclizine can be used with metoclopramide but this should be discussed with the ward pharmacist. Can be useful in vomiting due to raised intracranial pressure, intractable vomiting due to vestibular disorders, palliative care, irradiation sickness or opiate-induced vomiting. Side effects: Drowsiness, dry mouth, blurred vision and rash. 5 HT 3 antagonist. Treat/prevent acute and delayed CINV. Can be used instead of ondansetron if other first line therapies failed/unsuitable; Can give total daily dose as continuous IV infusion if effect wears off between doses. Side effects: Constipation, headache, rash and transient increase in liver enzymes. Drug of choice for vomiting due to renal/hepatic failure, and hypercalcaemia. Useful in opiate induced vomiting or intractable vomiting in palliative care. Side effects: Less sedating, extrapyramidal symptoms including dystonic reactions and akathisia A phenothiazine with effects at dopamine (D 2 ), histamine (H 1 ), muscarinic and 5HT 2 receptors. Can be useful in vomiting due to raised intracranial pressure. Has moderate sedating action. Used for delayed and refractory nausea and vomiting. Side effect: Sedation can be significant. Postural hypotension and constipation. Injection site reaction and occasionally raised ESR occurs. Carefully monitor patients receiving Ifosfamide since sedation may mask signs of encephalopathy. Dose: includes route and frequency. Oral / IV 1 month 6 years mg/kg three times a day (max. single dose 25mg) 6-12 years 25mg three times a day years 50mg three times a day Oral: 20micrograms/kg (max 1mg) twice to three times a day IV 40micrograms/kg (max 3mg) twice to three times a day Oral >12 years 1.5mg once daily at night; increased to twice a day if necessary, up to a maximum of 5mg twice a day IV / SC continuous infusion 25-85micrograms/kg (max 5mg) over 24 hours Oral 2-12 years mg/kg (max 25mg) once or twice a day. >12 years mg once or twice a day. SC / IV bolus doses mg/kg twice a day or 0.1mg/kg daily IV / SC continuous infusion micrograms/kg (max 25mg) over 24 hours Jenni Hatton Page 8 of 12 Version 5 May 2015

9 Drug and Preparation Lorazepam Tablets 1mg, 2.5mg Injection 4mg/ml (can be given sublingually). Indication, action, side effects and general comments A short acting benzodiazepine with minimal anti-emetic effects but can be used for its amnesic and anxiolytic properties. It has been used for anticipatory nausea and vomiting the night before chemotherapy is due. Enhanced sedation or respiratory and cardiovascular depression may occur if benzodiazepines are given with CNS depressants e.g. anaesthetics, opioids, antihistamines and anxiolytics. Dose: includes route and frequency. Oral >12 years 1-2mg once or twice a day Anticipatory nausea/vomiting aged 5-10 years: 0.5mg as a single dose. Give the night before and/or the morning of chemo. Breakthrough emesis: micrograms/kg/dose 6 hourly (max 4mg dose, but 2mg often sufficient) Nabilone Capsule 1mg Prochlorperazine Oral Syrup 5mg/5ml Tablets 5mg Buccal Tablets 3mg Injection 12.5mg/ml Hyoscine Hydrobromide patches Scopoderm TTS 1mg/72 hours release transdermal patch A cannabinoid drug with central action. Used in adolescents when refractory to dexamethasone and ondansetron. It is used for acute, delayed and refractory emesis. Start the night before, duration of chemo and until 48 hours after chemo. Side effects: dizziness, drowsiness, behavioural alterations, dry mouth, ataxia, postural hypotension. Hallucinations, euphoria and other psychotic reactions in some patients. Patients and carers should be made aware of possible changes in mood and other adverse behavioural effects. Dopamine agonist that acts centrally and blocks CTZ. Useful in opioid induced nausea and vomiting. Used for refractory anticipatory emesis and intractable vomiting of unknown cause. Anticholinergic muscarinic antagonist. It is used for refractory chemotherapy induced nausea and vomiting. Use with care in patients on other anticholinergic and CNS acting drugs. Prokinetic effect of metoclopramide and domperidone is antagonised. Side effects: drowsiness, dry mouth, dizziness, blurred vision, difficulty with micturition. Local irritation so rotate application site. Oral <18kg 0.5mg twice a day 18-30kg 1mg twice a day >30kg 1mg three times a day Oral 1-12 years 250micrograms/kg (max 10mg) three times a day >12 years 5-10mg three times a day BUCCAL >12 years 3-6mg twice a day IM 2-5 years 1.25mg - 2.5mg three times a day 5-12 years mg three times a day >12 years 12.5mg TDS 1 month to 3 years 250 microgram /72 hour (1/4 patch) 3-10 years 500 microgram/72 hours (1/2 patch) years 1mg/72 hours 1 patch Apply 12 hours before chemotherapy. Patches can be cut with scissors and applied to hairless skin behind ear. Jenni Hatton Page 9 of 12 Version 5 May 2015

10 Clinical Assessment The assessment of children and young people with chemotherapy-induced nausea and vomiting (CINV) can be difficult and complex. Children may not understand what they are being asked to describe, particularly in relation to nausea, and/or may not have the vocabulary to explain the symptoms they are experiencing. Therefore, discuss these issues with the nursing team and parents to assess children for signs and symptoms of CINV. History Key areas/questions to consider when taking a history from the child, parent and/or nurse include: Have they experienced any anticipatory vomiting (vomiting that usually occurs up to 12 hours before chemotherapy is commenced)? Has the child experienced CINV previously? Has previous antiemetic therapy been effective? Is the child or young person particularly anxious about their treatment or CINV? If so, the use of distraction and relaxation techniques, complementary therapies, psychological input and/or lorazepam may need to be considered and discussed with senior medical staff. Has the child experienced any change in appetite or mood that coincides with chemotherapy treatment? In pre-verbal children, these could be indicators of significant nausea. On examination When examining a child for signs and symptoms of CINV, the following may be evident: Pallor Tachycardia Dizziness Perspiration Anorexia Excess salivation Dehydration It is essential to assess the child s fluid balance, not only to identify dehydration but to ascertain whether the antiemetic therapy is successful or is in need of modification as per Figure 3. Follow up The efficacy and needs for antiemetic therapy should be reviewed by the clinical team at least every three months while on a chemotherapy regime. Discharge medication Regular antiemetics should be continued for the duration of chemotherapy and for 3 days afterwards. Children receiving low emetogenic chemotherapy do not require further antiemetic medication, unless they have experienced previous problems with delayed vomiting. Children receiving moderately emetogenic chemotherapy should initially be given a course of ondansetron to continue for two days after the end of chemotherapy. Children under 12 years of age receiving highly emetogenic chemotherapy should be given ondansetron with dexamethasone (unless the latter contraindicated). Dexamethasone should only be given for a total of 5 days. A five-day supply of domperidone to be taken when required should also be prescribed and dispensed. Children under 12 years of age receiving very highly emetogenic chemotherapy should be given ondansetron with dexamethasone (unless the latter contraindicated). Dexamethasone should only be given for a total of 5 days. A five-day supply of metoclopramide to be taken only if needed should also be prescribed and dispensed. Jenni Hatton Page 10 of 12 Version 5 May 2015

11 Children 12 years and older receiving highly or very highly emetogenic chemotherapy will have aprepitant for up to seven days to cover the course of chemotherapy plus 2 further days. They should also be given a supply of ondansetron and dexamethasone (unless the latter is contraindicated as above). If vomiting persists for longer than 7 days then metoclopramide or domperidone should be used as these are more effective than 5HT 3 antagonists for long term use. References 1. Emend 80mg and 125mg hard capsules. Summary of Product Characteristics. Available at accessed 19 th January Joint Formulary Committee. BNFc London, BMJ Group, RPS Publishing, PCPCH Publishing 3. Hawkins R and Grunberg S. Chemotherapy-induced nausea and vomiting: challenges and opportunities for improved patient outcomes. Clin J Onc Nursing 2009; 13(1): National Institute for Health and Clinical Excellence. Improving outcomes in children and young people with cancer. Available at accessed 15 th December Dupuis L and Nathan P. Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Pediatr Drugs 2003; 5(9): Tramer M et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001; 323: Smith A et al. Aprepitant for the control of chemotherapy induced nausea and vomiting in adolescents. Pediatr Blood Cancer 2005; 45: Schmoll H et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Onc 2006; 17: Antonarakis E et al. Prophylaxis of acute chemotherapy-induced nausea and vomiting in children with cancer: what is the evidence? Pediatr Blood Cancer 2004; 43: Holdsworth M et al. Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer 2006; 106(4): Roila F et al. Prevention of chemotherapy and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Onc 2006; 17: Molassiotis A et al. A prospective observational study of chemotherapy-related nausea and vomiting in routine practice in a UK cancer centre. Support Care Cancer 2008; 16: Small B et al. Survey ranking of emetogenic control in children receiving chemotherapy. J Ped Hem/Onc 2000; 22(2): Schnell F. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. The Oncologist 2003; 8: Jordan K, Sippel C and Schmoll H. Guidelines for antiemetic treatment of chemotherapyinduced nausea and vomiting: past, present and future recommendations. The Oncologist 2007; 12: Hesketh P. Chemotherapy-induced nausea and vomiting. N Eng J Med 2008; 358(23): Giglio A et al. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapyinduced nausea and vomiting. Cancer 2000; 89(11): Jassal SS, Hain R. The Association of Paediatric Palliative Medicine Master Formulary Jenni Hatton Page 11 of 12 Version 5 May 2015

12 Appendix 1: Graph to show relative costs of 24 hours antiemetic therapy. APREPITANT 125mg OD APREPITANT 80mg OD Dexamethasone 2mg TDS IV Dexamethasone 2mg TDS PO TAB Dexamethasone 4mg TDS IV Dexamethasone 4mg TDS PO TAB Domperidone 10mg TDS PO SYRUP Domperidone 10mg TDS PO TAB Domperidone 5mg TDS PO SYRUP Domperidone 5mg TDS PO TAB Granisetron 1mg BD IV Granisetron 1mg BD PO TAB Granisetron 3mg TDS IV Haloperidol 1.5mg PO OD TAB Lorazepam 1mg BD PO TAB Metoclopramide 10mg TDS IV Metoclopramide 10mg TDS PO SYRUP Metoclopramide 10mg TDS PO TABS Metoclopramide 5mg TDS IV Metoclopramide 5mg TDS PO SYRUP Metoclopramide 5mg TDS PO TABS Nabilone 0.5mg BD PO Nabilone 1mg BD PO Ondansetron 2mg TDS IV Ondansetron 2mg TDS PO SYRUP Ondansetron 2mg TDS PO TABS Ondansetron 4mg TDS IV Ondansetron 4mg TDS PO SYRUP Ondansetron 4mg TDS PO TABS Jenni Hatton Page 12 of 12 Version 5 May 2015