Conflicts of Interest. Review of Antiemetic Guidelines. Learning Objectives. What is Emesis Anyways? Pharmacy Technician Learning Objectives

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1 Conflicts of Interest No financial relationships to disclose Review of Antiemetic Guidelines Matthew Fox, PharmD, BCPS, BCOP Clinical Oncology Pharmacist Baptist MD Anderson Jacksonville, Florida October 22, 2017 Learning Objectives Assess risk factors for chemotherapy induced nausea and vomiting (CINV) Develop an appropriate premedication regimen for moderately emetogenic (MEC) and highly emetogenic (HEC) chemotherapy agents Identify breakthrough treatment options for patients based on drug classifications Pharmacy Technician Learning Objectives Recognize the appropriate dosage form for antiemetic medications Identify breakthrough treatment options for patients based on drug classifications Devise a plan for medication preparation regarding chemotherapy regimens What is Emesis Anyways? Nausea is a subjective term describing the inclination to vomit. Often accompanied by a loss of gastric tone, pallor, and salivation Vomiting/Emesis is the expulsion of gastric content through the mouth Retching is the contraction of the abdominal wall, diaphragm, and thoracic muscle without an expulsion of content Patient s Perception of Most Severe Side Effects Rank Vomiting Nausea Nausea Fatigue 2 Nausea Loss of hair Loss of hair Nausea 3 Loss of hair Vomiting Constantly tired Sleep Disturbances 4 Thought of upcoming treatment Constantly tired Vomiting Weight loss 5 Lengthof time treatment takes Having to have an injection Changes in the way things taste Loss of hair Coates A, et al. Eur J Cancer Clin Oncol. 1983; 19: de Boer Dennert M, et al. Br J Cancer. 1997;76: Lindley C, et al CancerPract. 1999;7: Hofman M, et al. Cancer. 2004;101:

2 Impact of Uncontrolled CINV Types of CINV Treatment Outcome Decreased Adherence Increased Medical Cost $1,300/month Ineffective Control of CINV Economic Burden Lost Work Days 6.23 work days/month Quality of Life Decreased Activities of Daily Living Acute: nausea or emesis occurring within the first 24 hours of chemotherapy treatment Delayed: nausea or emesis occurring hours after chemotherapy Anticipatory: nausea or emesis often triggered by sights, smells, or sounds prior to chemotherapy administration Breakthrough: nausea or emesis despite antiemetic prophylaxis Shih, YCT, Cancer; 2007 Pathophysiology Improvements in CINV Key SP = Substance P CTZ = chemoreceptor trigger zone M = muscarinic D2 = dopamine NK1 = neurokinin 5 HT3RA= serotonin receptor antagonist Perwitasari DA, et al. Int J Clin Pharm :33 43 Risk factors Female Younger than 50 years old History of low chronic alcohol use History of morning sickness Motion sickness Anxiety Prior chemotherapy with poor antiemetic control Multiple classes of antiemetics available Molassiotis A, Aapro M, Dicato M, et al. J Pain Symptom Manage Sep 24 Improvements in CINV National and international guidelines National Comprehensive Cancer Network (NCCN) American Society of Clinical Oncology (ASCO) Multinational Association of Supportive Care in Cancer (MASCC)/ European Society of Medical Oncology (ESMO) Prebuilt chemotherapy regimens containing supportive care options Guidelines 2

3 Emetogenic Potential Classification Based on single agent risk High (Greater than 90%) Moderate (30 90%) Low (10 30%) Minimal (Less than 10%) Multidrug regimens are classified by the drug with the highest emetogenicty risk Emetogenic Potential of Intravenous Antineoplastics Emotogenic Potential of Intravenous Antineoplastics Emotogenic Potential of Oral Antineoplastics Serotonin Receptor Antagonist Serotonin Receptor Antagonist Agent Route Dose Ondansetron IV Oral 8 mg 16 mg 8 mg 24 mg Granisetron IV Subcutaneous Oral Transdermal patch 1mg (maximum) 10 mg 2 mg 3.1 mg/24 hour Dolasetron Oral 100 mg Palonosetron IV 0.25 mg Blocks 5 HT 3 peripherally in the gastrointestinal tract and centrally in the medulla Adverse effects: QTC prolongation (except palonosetron), headache, constipation 3

4 Neurokinin 1 Receptor Antagoinist Agent Route Dose Aprepitant Oral 125 mg on Day 1 then 80 mg Daily for two days Fosaprepitant IV 150 mg Rolapitant Oral 180 mg Netupitant Oral 300 mg in combination with palonestron Neurokinin 1 Receptor Antagoinist Inhibits substance P to prevent acute and delayed vomiting Adverse effects Hiccups, reflux symptoms, dizziness, weakness, headache Drug/Drug Interactions Dexamethasone (except rolapitant), warfarin, oral contraceptives Corticosteroids Dexamethasone Dose range from 4 20 mg Inhibit prostaglandin synthesis in the cortex Limit inflammation in gastrointestinal tract Adverse effects Insomnia/hyperactivity, anxiety, increased appetite, hyperglycemia Adding steroids to 5 HT 3 RA increases their efficacy by as much as 20% Effective in preventing delayed CINV Phenothiazines Drug Route Dose Prochlorperazine IV Oral Rectal 5 10 mg 5 10 mg 25 mg Promethazine IV Oral Rectal mg mg mg Block dopamine receptors in the CTZ Adverse effects: drowsiness, hypotension, akathisia, dystonia Lohr L. Chemotherapy induced nausea and vomiting. Cancer J. 2008;14:85 93 Substituted Benzamines Metoclopramide Dose 1 mg/kg 2 mg/kg IV, 0.5 mg/kg Oral Blockade of dopamine receptors in CTZ Stimulation of cholinergic activity in the gut Antagonism of peripheral serotonin receptors Adverse effects Diarrhea, extrapyramidal symptoms, mild sedation Benzodiazepines Lorazepam 0.5 mg 2 mg oral/iv Binds on the postsynaptic GABA neuron enhancing the inhibitory effect of GABA on neuron excitability Relieves anxiety, anterograde amnesia Adverse effects Sedation, hypotension, disorientation 4

5 Cannabinoids Dronabinol mg by mouth Nabilone 1 2 mg by mouth Activates cannabinoid receptor CB1 within the central nervous system Adverse Effects Drowsiness, dizziness, orthostatic hypotension, ataxia, hallucinations, time disorientation Atypical Antiphysicotic Olanzapine Dose 5 10 mg by mouth Off label use for prevention of nausea/vomiting Blocks multiple neurotransmitters, including dopamine, serotonin, histamine, and muscarinic receptors Adverse Effects sedation, QTc prolongation, dry mouth, increased appetite, weight gain, postural hypotension, dizziness Hashimoto H: 2016 Highly Emetogenic Chemotherapy (HEC) Highly Emetogenic Chemotherapy Drug ASCO NCCN MASCC/ESMO NK1 RA Yes Yes Yes 5HT3 RA Yes Yes Yes Dexamethasone Yes Yes Yes Olanzapine Yes Depends For delayed chemotherapy HEC prophylaxis must cover acute (0 24 hours) and delayed ( hours) CINV Highly Emetogenic Chemotherapy Phase III Randomized Control Trial of Olanzapine in Highly Emetogenic Chemotherapy Primary endpoint No Nausea Secondary endpoint Complete response (no emesis/no use of rescue medications) All patients received NK1 RA (aprepitant or fosaprepitant) Dexamethasone 8 mg days 2 4 Olanzapine/placebo 10 mg days 2 4 Navari R:

6 Phase III Trial of Olanzapine in Highly Emetogenic Chemotherapy Endpoint Olanzapine Arm Placebo Arm P value No acute nausea No delayed nausea No overall nausea CR: Acute CR: Delayed CR: Overall 74% 42% 37% 86% 67% 64% 45% 25% 22% 65% 52% 41% < < <0.001 Moderately Emetogenic Chemothrapy Drug ASCO NCCN MASCC/ESMO NK1 RA May add Yes With carboplatin 5HT3 RA Yes Yes Yes Dexamethasone Yes Days 1 3 YesDay 1, +/ Day 2 3 Yes Olanzapine No May substitute NK1 RA No ASCO Recommendations for MEC No grade 3 or 4 toxicities attributed to olanzapine by the attending clinician Sedation was significant in the olanzapine arm on day 2, but resolved on days 3, 4, and 5 Navari R: 2016 NCCN Recommendations for MEC Low Emetogenic Chemotherapy Administer one antiemetic of choice prior to chemotherapy Dexamethasone Prochlorperazine 5 HT3 RA of choice once Minimally Emetogenic Chemotherapy No antiemetic routinely scheduled, PRN recommended Miscellaneous Types of Emesis Perception of Most Severe Side Effects Anticipatory CINV Prevention is key Lorazepam Hypnosis Relaxation Breakthrough CINVU Use a different antiemetic class Procholoperazine Metoclopramide Olanzapine Consider around the clock dosing Reassess antiemetics prior to next cycle of chemotherpay Rank Vomiting Nausea Nausea Fatigue 2 Nausea Loss of hair Loss of hair Nausea 3 Loss of hair Vomiting Constantly tired Sleep Disturbances 4 Thought of upcoming treatment Constantly tired Vomiting Weight loss 5 Lengthof time treatment takes Having to have an injection Changes in the way things taste 5 HT 3 RA 5 HT 3 RA + dexamethasone Loss of hair NK1 inhibitors Coates A, 1983; De Boer Dennert M, 1997; Lindley 1999; Hofman M,

7 Challenges with CINV Inappropriate antiemetic regimen prescribed Patient reporting Adherence Cost Challenges with CINV Guidelines typically only consider one agent Patient not addressed Risk factors Maintenance medications Other causes of nausea/vomiting Other Causes of Nausea/Vomiting Gastrointestinal Electrolyte imbalances Pain Vestibular dysfunction Brain metastases Non Pharmacologic Treatment Diet Avoid spicy, greasy, salty foods Eat smaller meals Hydration Restful sleep Acupunture/Acupressure Cognitive distraction Available Tools MASCC Antiemesis Tool Time to Talk CINV From Hematology/Oncology Pharmacy Association Provides patient prompting and education Available Tools 7

8 Self Assessment Question A.C. is a 68 year old male with NSCLC. He is at the clinic today for chemo clearance prior to starting maintenance pemetrexed, which has low emetogenicity. He tells you that he had no problems with nausea while he was on combination treatment carboplatin/pemetrexed. What is the best choice for CINV prophylaxis for A.C.? A. Nothing B. Fosaprepitant 150 mg IV + Ondansetron 16 mg IV + Dexamethasone 10 mg IV C. Dexamethasone 10 mg IV Push D. Netupitant 300 mg/palonosetron 0.5 mg PO + Olanzapine 10 mg PO + Dexamethasone 20 mg IV Self Assessment Question Which of the following lessens a patient s risk of having chemotherapy induced nausea and vomiting? A. Young B. Female C. History of motion sickness D. Chronic alcohol intake Self Assessment Question L.M. is a 45 year old single mother that had great deal of N/V after her second round of chemotherapy. The thought of getting chemotherapy today makes her nauseous. What is the most appropriate regimen for her? A. Ondansetron + dexamethasone B. Fosaprepitant + ondansetron + dexamethasone + lorazepam C. Rolapitant + metoclopramide D. None of the above References Coates A. et al. Eur J Cancer Clin Oncol. 1983; 19:203 8 De Boer Dennert M, et al. Br J Cancer. 1997; 76: Lindley C, et al. Cancer Pract. 1999; 7:59 65 Hofman M. et al. Cancer 2004; 101: Perwitasari, Dyah & Gelderblom, Hans & Atthobari, Jarir & Mustofa, Mustofa & Dwiprahasto, Iwan & W R Nortier, Johan & Guchelaar, Henk Jan. Anti emetic drugs in oncology: Pharmacology and individualization by pharmacogenetics. International journal of clinical pharmacy. 2001; Shih, Y.C.T., Xu, Y., & Elting, L.S. Costs of uncontrolled chemotherapy induced nausea and vomiting among workingage cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer 2007; 110(3), Lohr L. Chemotherapy induced nausea and vomiting. Cancer J. 2008:14: Molassiotis A, Aapro M, Dicato M, et al. J Pain Symptom Manage May; 47(5): Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy induced nausea and vomiting: a meta analysis of randomized evidence. J Clin Oncol 2000; 18:3409. Hashimoto H, Yanai T, Nagashima K, et al. A double blind randomized phase II study of 10 versus 5 mg olanzapine for emesis induced by highly emetogenic chemotherapy with cisplatin [abstract]. J Clin Oncol 2016;34 Abstract Navari R, Quin R, Ruddy K, Liu H, Powell S, Bajaj M, Dietrich L, Biggs D, Lafky J, Loprinzi C. Olanzapine for the Prevention of Chemotherapy Induced Nausea and Vomiting. N Engl J Med 2016; 375: Roila F, Molassiotis A, Herrstedt J, et al MASCC and ESMO guideline update for the prevention of chemotherapy and radiotherapy induced nausea and vomiting in advanced cancers patients. Annals of Oncology 2016; 27(5):v119 v133. NCCN. Referenced with permission from the national comprehensive cancer network, clinical practice guideline in onocology antiemesis v NCCN Accessed [August 28, 2017]. Hesketh PJ, Kris M, Basch E, et al. Antiemetics: American society of clincical oncology clinical practice guideline update. Journal of Clincial Oncology :28,