1. Evidence, Challenges and Solutions: Preventing and Managing Chemotherapy- Induced Nausea and Vomiting Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008

2. Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy Rank1983 1 1993 2 1995 3 1999 4 1.VomitingNausea 2.NauseaConstantly tiredLoss of hair 3.Loss of hair VomitingConstantly tired 4.Thought of coming for treatment Effect on familyConstantly tiredVomiting 5.Length of time treatment takes VomitingHaving to have an injection Changes in the way things taste Adapted from: 1 Coates A et al. Eur J Cancer Clin Oncol. 1983;19:203-8. 2 Griffin AM et al. Ann Oncol. 1996;7:189-95. 3 De Boer-Dennert M et al. Br J Cancer. 1997;76:1055-61. 4 Lindley C et al. Cancer Pract 1999;7:59-65.

3. CINV - Definitions Acute – within a few minutes to several hours after drug administration and commonly resolves within 24 hours. Delayed – develops in patients more than 24 hours after chemotherapy administration. May last up to 6 days It commonly occurs with cisplatin, carboplatin, cyclophosphamide and/or anthracyclines. Anticipatory – nausea and/or vomiting before patients receive their chemotherapy, after a prior negative experience with chemotherapy Breakthrough – occurs despite prophylactic treatment and/or requires rescue. Refractory – nausea and emesis during subsequent cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles Adapted from: 1. ASHP Am J Health Syst Pharm 1999;56:729-764 2. NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis

4. Rates of CINV Adapted from: 1. Hickok JT, et al. Cancer. 2003;97:2880-6. 2.http://www.ashpadvantage.com/previous_meetings/mcm_2005/cemornings2005/CEM_CINV_handout.pdf

5. Chemotherapy-Induced Emesis Risk Factors Patient-related risk factors include: Younger age Female gender No/minimal prior history of alcohol use Prior CINV Anxiety High pretreatment expectation of severe nausea Adapted from: 1.Gregory RE et al. Drugs. 1998.; 2. Hesketh PJ et al. J Clin Oncol. 1997. 2.Roscoe JA, Bushunnow P, Morrow GR, et al. Patient experience is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer 2004;101:2701-2708

6. Influence of Patient Expectations on CINV Expectancy of nausea assessed before patients received their first doxorubicin-based chemotherapy treatment was found to be a strong predictor of subsequent nausea. Adapted from Roscoe et al. Cancer. 2004 101(11):2701-8.

7. Chemotherapy-Induced Emesis Risk Factors Treatment-related risk factors include: High drug dose High emetogenicity of chemotherapy drugs Of all the known predictive factors, the emetogenicity of a given chemotherapeutic agent is the predominant factor. Adapted from ASHP Am J Health Syst Pharm 1999;56:729-64.

8. Causes of CINV In addition to emesis induced by chemotherapy, CINV can be caused by: Partial or complete bowel obstruction Vestibular Dysfunction Brain Metastases Electrolyte imbalance: hypercalcemia, hyperglycemia, hyponatremia, uremia Concomitant drugs, including opiates Gastroparesis induced by a tumor or chemotherapy (such as vincristine) Psychophysiologic factors, including anxiety as well as anticipatory nausea and vomiting Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.

9. Consequence of Unresolved CINV Discontinuation of therapy Serious metabolic derangements Nutritional depletion and anorexia Esophageal tears Wound dehiscence Deterioration of patients’ physical and mental status Degeneration of self-care and functional ability Adverse sequelae of nausea and vomiting in the cancer patient. Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.

10. Poll of the audience As Health care professionals we often : A. Accurately recognize the incidence of acute and delayed CINV in our own practices. B. Underestimate the incidence of acute and delayed CINV in our own practices.

11. Anti Nausea Chemotherapy Registry (ANCHOR) study The authors determined the incidence of acute and delayed CINV after modern antiemetics. Then they compared the actual incidences of CINV to the predictions made by physicians and nurses regarding these patients. Adapted from Grunberg SM et al. Cancer 2004;100:2261-8.

12. Anchor Study Perception vs Reality Moderately Emetogenic Chemotherapy Adapted from Grunberg et al. Cancer 2004;100:2261-8.

13. Toxicity Assessments Grade common toxicity effects of adjuvant breast cancer patients. Patients are assessed the day of chemotherapy and again 2-3 days post chemotherapy. Patients also have a number to call back if they experience any toxicities. Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland

14. Rates of CINV in N=26 Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland

15. Rate of CINV Adapted from Cancer 2004;100:2261-8. N=231 at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland in comparison to the Grunberg data

16. Health Care Professionals Perception of CINV at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland Adapted from Cancer 2004;100:2261-8.

17. CINV—Decreased Quality of Life CINV adversely impact patients' quality of life. Ovarian cancer patients in a recent study included complete to almost complete control from CINV among the most favorable health states, just below perfect health and clinical remission. Adapted from Support Care Cancer 2005;13:219-27.

18. CINV—Decreased Quality of Life Adapted from Support Care Cancer 2005;13:219-27.

19. Adapted from Bloechl-Daum B et al. J Clin Oncol. 2006;24:4472. CINV—Decreased Quality of Life FLIE Questionnaire HEC-FLIE > MEC-FLIE P=0.0049 FLIE-nausea > FLIE-Vomiting P=0.0097 There is a greater negative impact on QOL from nausea than there is from vomiting There is a greater negative impact on QOL from HEC than there is from MEC FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.

20. Summary of the Importance of Prevention and Treatment of CINV There still is a high level of anguish for CINV experienced by our patients. As health care professionals, we may not be accurately predicting the level of CINV experienced by our patients. CINV has a enormous impact on our patients quality of life.

21. Mechanisms of CINV Central mechanism: Chemotherapeutic agent activates the chemoreceptor trigger zone (CTZ). Activated CTZ invokes release of various neurotransmitters, which stimulate vomiting center. Peripheral mechanism: Chemotherapeutic agent causes irritation and damage to gastrointestinal (GI) mucosa, resulting in the release of neurotransmitters. Activated receptors send signals to vomiting center via vagal afferents. Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869–2880.

22. Adapted from N Engl J Med 2008;358:2482-94.

23. Serotonin and 5-HT 3 Receptor Pathway First recognized with high-dose metoclopramide. Development of 5-HT 3 antagonists has had dramatic impact: Highly effective in acute vomiting, less effective for delayed events. Optimal use is with dexamethasone. Primary mechanism of action appears to be peripheral. Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869-80. Gralla RJ et al J Clin Oncol 1999;17:2971-94. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811-19. Endo T et al Toxicology 2000;153:189-201. Hesketh PJ et al Eur J Cancer 2003;39:1074-80.

24. Substance P and Neurokinin­1 (NK 1 ) Receptor Pathway High density of substance P/NK 1 receptors located in brain regions implicated in the emetic reflex. Primary mechanism of NK 1 receptor blockade action appears to be central. Effective for both acute and delayed events. Augments antiemetic activity of a 5-HT 3 receptor antagonist and corticosteroid. Adapted from: Hargreaves R J Clin Psychiatry 2002;63(suppl 11):18-24. Saria A Eur J Pharmacol 1999;375:51-60. Hesketh PJ Support Care Cancer 2001;9:350-54.

25. Conceptual Model of Acute & Delayed CINV Adapted from Andrews & Davis. In: Andrews PLR & Sanger GJ (Eds). Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London: Arnold; 1993:147. 5-HT 3 -sensitive phase Prokinetic-sensitive phase Steroid-sensitive phase Disrupted gut motility Cell breakdown products Intensity of emesis Time (days) 0 1 2 345 5HT NK 1 -sensitive phase

26. Pharmacogenomics Quest for individualized therapy. Identification and characterization of a large number of genetic polymorphisms(biomarkers) in drug metabolizing enzymes and drug transporters may provide substantial knowledge about the mechanisms of inter-individual differences in drug response.

27. Pharmacogenomics Pharmacogenomics - the study of the relationship between specific DNA sequence variations and the actual effect of a drug. CYP2D6 is involved in the metabolism of all of the most commonly available serotonin antagonists, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. As this enzyme is polymorphic, several different alleles may be present in different individuals.

28. Number of Subjects Increasing Metabolic Capacity EM PM URM Pharmacogenomics Polymorphic Distribution  CYP2D6 mutations or deletions, poor metabolizer (PM), occur in 10% of the general population  (UM) Ultrarapid metabolizer phenotype is observed in 2% of the general population.  EM (extensive metabolizer), which is the normal or usual phenotype.

29. Pharmacogenomics in CINV Kaiser studied the impact of patient genotype for 2D6 (CYP2D6) on efficacy of ondansetron and tropisetron for CINV. The ultrarapid metabolizer patients experienced significantly more nausea and vomiting after chemotherapy. The impact of genotype on vomiting incidence was observed during both early (hours 0 to 4) and late (hours 5 to 24) observation periods, although delayed nausea and vomiting was not evaluated in this study. Adapted from: Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 20: 2805-11, 2002.

30. Figure 2. Mean number of episodes of vomiting ({+/-} standard deviation) experienced 5-24 hours after chemotherapy as a function of the number of active cytochrome P450 CYP2D6 enzyme genes in patients receiving tropisetron, 5 mg once a day (A), and ondansetron, 8 mg twice a day (B) Pharmacogenomics in CINV Adapted from: Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 20:2805-11, 2002.

31. ANTIEMETIC GUIDELINE CONSENSUS - Official Process Subscribed to by 9 International Oncology Groups - International:MASCC North America: - U.S.ASCO, NCCN - CanadaCCO Europe:ESMO, EONS Africa:SASMO Australia:COSA Adapted from MASCC Antiemetic March 2008 Guideline Update.

32. MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES ANTIEMETIC TREATMENT GUIDELINES - The Four Emetic Risk Groups - HIGH Risk in nearly all patients (> 90%) MODERATE Risk in 30% to 90% of patients LOW Risk in 10% to 30% of patients MINIMAL Fewer than 10% at risk Adapted from MASCC Antiemetic March 2008 Guideline Update.

33. MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES - Emetic Risk Groups - Single IV Agents - HIGH Cisplatin Mechlorethamine Streptozocin Cyclophosphamide > 1500 mg/m 2 Carmustine Dacarbazine MODERATE Oxaliplatin Cytarabine >1 gm/m 2 Carboplatin Ifosfamide Cyclophosphamide <1500 mg/m 2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan Adapted from MASCC Antiemetic March 2008 Guideline Update.

34. MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES - Committee I (3/5): Emetic Risk Groups - Single IV Agents LOW Paclitaxel Docetaxel Mitoxantrone Topotecan Etoposide Pemetrexed Methotrexate Doxorubicin HCL liposome injection Mitomycin Gemcitabine Cytarabine <100 mg/m 2 5-Fluorouracil Bortezomib Cetuximab Trastuzumab Adapted from MASCC Antiemetic March 2008 Guideline Update.

35. MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES ANTIEMETIC TREATMENT GUIDELINES - Committee I (5/5): Emetic Risk Groups - Single Oral Agents - HIGHHexamethylmelamineProcarbazine MODERATE CyclophosphamideEtoposideTemozolomideVinorelbineImatinib LOW Capecitabine Tegafur uracil MINIMAL ChlorambucilHydroxyurea L-Phenylalanine mustard 6-ThioguanineMethotrexateGefitinib Adapted from MASCC Antiemetic March 2008 Guideline Update.

36. Principles of Care for Acute Highly and Moderately Emetic Settings UNANIMOUS CONSENSUS: CATEGORY 1 EVIDENCE - Use the lowest tested fully effective dose. - No schedule is better than a single dose given before chemotherapy. - The antiemetic efficacy and adverse effects of serotonin antagonist agents are comparable in controlled trials. - Intravenous and oral formulations are equally effective and safe. - Always give dexamethasone with a 5-HT 3 antagonist before chemotherapy. Adapted from MASCC Antiemetic March 2008 Guideline Update.

37. To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen is recommended including single doses of: 5-HT 3 antagonist Dexamethasone Aprepitant (or fosaprepitant) given before chemotherapy is recommended. MASCC Level of confidence : High MASCC Level of consensus: High ASCO Level of evidence: I ASCO Grade of recommendation: A Adapted from slide from MASCC Antiemetic March 2008 Guideline Update. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk:

38. Example - Women receiving a combination of anthracycline + cyclophosphamide represent a situation with a particularly great risk of vomiting and nausea. To prevent acute vomiting and nausea in these women, a three-drug regimen including single doses of: 5-HT 3 antagonist Dexamethasone Aprepitant (or fosaprepitant) given before chemotherapy is recommended. MASCC Level of confidence: Moderate MASCC Level of consensus: High ASCO Level of evidence: II ASCO Grade of recommendation: A Adapted from MASCC Antiemetic March 2008 Guideline Update. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC):

39. In patients who receive MEC, not including a combination of anthracycline plus cyclophosphamide: 5-HT3 receptor antagonist + Dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course. MASCC level of confidence: High MASCC level of consensus: High ASCO level of evidence: I ASCO grade of recommendation: A Adapted from MASCC Antiemetic March 2008 Guideline Update. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC):

40. B.C. Cancer Agency Antiemetic regimens Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32- 5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf

41. ONS Putting Evidence into Practice Adapted from ONS PEP Nausea Retrieved July 21, 2008 from http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf

42. ONS Putting Evidence into Practice – Cont’d

43. Cancer Care Ontario - Telephone Nursing Practice - and Symptom Management Guidelines Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf

44. Cancer Care Ontario - Telephone Nursing Practice and Symptom Management Guidelines Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf

45. Common CINV Challenges Challenges in multiple-day chemotherapy regimens Breakthrough CINV Anticipatory CINV Delayed CINV

46. Multiple-Day Chemotherapy Regimens Challenge – Patients receiving multi-day chemotherapy (chemotherapy administered over several days per cycle) are at risk for both acute and delayed nausea and vomiting. It is difficult to recommend appropriate antiemetics for each day since acute and delayed may overlap after the initial day of chemotherapy. The period of risk for delayed nausea and vomiting also depends on the emetogenic potential of the last chemotherapy agent administered in the regimen. Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

47. Multi-Day Chemotherapy Regimens (continued) A 5-HT3 receptor antagonist should be administered prior to each days 1 st dose of moderately or highly- emetogenic chemotherapy. Dexamethasone should be administered once daily either orally or IV for every day of chemotherapy and for 2-3 days post chemotherapy. Aprepitant may be used for multi-day chemotherapy. Aprepitant 125 mg on day 1, then aprepitant 80 mg daily on days 2 and 3 along with dexamethasone. Based on Phase II data, aprepitant may be safely administered on days 4 and 5 after chemotherapy. Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

48. Breakthrough CINV Breakthrough emesis refers to vomiting that occurs despite prophylactic treatment and/or requires rescue. Refractory emesis refers to emesis that occurs during subsequent treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles. Challenge - Breakthrough nausea and vomiting represents a difficult situation as ongoing refractory nausea is hard to reverse. Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

49. Breakthrough CINV (continued) Management Strategies -Give around the clock administration versus prn. Additional agents should be from a different drug class than initial therapy. No one treatment is better than the other. Possibilities include: dopamine antagonists, metoclopramide, haloperidol, cannabinoids, corticosteroids, or agents such as lorazepam If patient has dyspepsia, consider antacid therapy (H2 blocker or Proton Pump Inhibitor). Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

50. Breakthrough CINV – Cont’d Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32- 5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf

51. Adapted from: 1. Roscoe JA, et al. J Pain Symptom Manage 2000;20:113. 2. Morrow GR, et al. Support Care Cancer 1998;6:244. Anticipatory CINV Anticipatory nausea and/or vomiting is the occurrence of nausea and/or vomiting before patients receive their chemotherapy treatment. Because it is a conditioned response, it can only occur after a negative past experience with chemotherapy. Challenge - Anticipatory nausea and/or vomiting occurs in 18% to 57% of chemotherapy patients. Younger patients may be more susceptible as they generally receive more aggressive therapy and have poorer emesis control than older patients.

52. Anticipatory CINV (continued) The most effective way to treat is to prevent CINV by using optimal antiemetics during every cycle of therapy. Either: Alprazolam PO 0.25 to 0.5 mg t.i.d. beginning on the night before treatment OR; Lorazepam 0.5-2 mg PO on the night before and the morning of treatment. Behavioral therapy Systemic densensitization Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

53. Adapted from Grunberg et al. Cancer 2004;100:2261. Delayed CINV Challenge - Delayed emesis is 2.5 times more prevalent than acute emesis. For moderately emetogenic chemotherapy: Delayed nausea exceeds acute nausea by 16%. Delayed emesis exceeds acute emesis by 15%. For highly emetogenic chemotherapy: Delayed nausea exceeds acute nausea by 27%. Delayed emesis exceeds acute emesis by 38%.

54. Prognostic Factors for Delayed CINV Strongest predictor of delayed nausea and vomiting was the occurrence of acute nausea and vomiting. Patients aged 52 years or younger and women were more likely to have delayed nausea than were those older than 52 years and men. A high expectation of nausea was a significant predictor of more severe nausea. Adapted from The Lancet Oncology October 2005;Vol(6):Issue(10):765-72.

55. Case 1 Initial Presentation Mary T. is a 56-year-old female who was completely asymptomatic when a routine mammogram showed two lesions. She underwent diagnostic testing and had a mastectomy and auxiliary lymph node dissection. Diagnosis – T3 (more than 5 cm) N0(0/6 lymph nodes) M0. poorly differentiated invasive ductal carcinoma of right breast, ER/PR positive and HER-2/neu negative.

56. Initial Presentation PAST MEDICAL HISTORY: Unremarkable. SOCIAL HISTORY: School teacher, married, mother of two grown children living away, non smoker, occasional drink on the weekends. MEDICATIONS: Ranitidine 150 mg b.i.d., Lorazepam 1 mg prn SYSTEM INQUIRY: Unremarkable. Allergies : NKA (drugs, food, environmental allergens)

57. First Cycle of Chemotherapy (FEC) The patient is prescribed FEC (Fluorouracil, Epirubicin, Cyclophosphamide) – for 3 cycles followed by Taxotere for 3 cycles. She was given Ondansetron 8 mg and Dexamethasone 8 mg prior to her first cycle of chemotherapy. She was given a prescription for Ondansetron 8 mg and Dexamethasone 4 mg po b.i.d. x 2 days post chemotherapy as well as Metoclopramide 10 mg po q6hprn to be taken post chemotherapy.

58. Nausea post Cycle 1 When she returned for cycle two she informed the pharmacist that she had vomited on day 2 and that she had experienced nausea for days 2-5 post chemotherapy. She rates this nausea as a 8/10 for days 2-4 and 6/10 for day 5.

59. Case 1: Question 1 What anti-emetics would you recommend to be given prior to chemotherapy for her second cycle of FEC? A.Metoclopramide 10 mg B.Ondansetron 8 mg, Dexamethasone 8 mg and Aprepitant 125 mg A.Ondansetron 8 mg and Dexamethasone 8 mg

60. Women receiving a combination of anthracycline + cyclophosphamide represent a situation with a particularly great risk of vomiting and nausea. To prevent acute vomiting and nausea in these women, a three-drug regimen including single doses of: 5-HT 3 antagonist Dexamethasone Aprepitant (or fosaprepitant) given before chemotherapy is recommended. Adapted from MASCC Antiemetic March 2008 Guideline Update. Answer Question 1 = B Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC):

61. Case 1: Question 2 What anti-emetics would be offered to this patient as an anti- nausea take home prescription for the FEC (cycle 2) regimen? A. Dexamethasone 8 mg bid x 3 days and Metoclopramide 10 mg q6hprn. B. Metoclopramide 10 mg q6hprn. C. Aprepitant 80 mg on days 2 and 3, Ondansetron 8 mg and Dexamethasone 4 mg bid x 2 days and Metoclopramide 10 mg q6hprn.

62. Answer Question 2 Adapted from http://www.bccancer.bc.ca.

63. Case 1: Question 3 What other actions can the pharmacist take to help M.T. control her CINV?

64. Answer Question 3 Explore patient adherence with anti-emetics. Assess effectiveness/ineffectiveness of anti-emetic plan. Follow up toxicity assessments (use CCO telephone toxicity guidelines). CINV education. Communication with her other health care providers. Patient nausea diary (CANO patient education for CINV). Promote patient involvement through patient resources: ► Chemotherapy and You: A Guide to Self-Help During Cancer Treatment, http://www.nci.nih.gov/cancerinfo/chemotherapy- and-you ► http://www.cancernausea.com

65. Case 1: Question 4 The pharmacist asks the patient what medications she is currently taking. She informs the nurse she is taking Warfarin, Metoprolol and ASA. Should she be concerned about a drug interaction with Warfarin and Aprepitant?

66. Case 1: Question 5 Which of the following may occur with the addition of aprepitant to M.T’s regimen? A. INR may decline B. INR may increase C. Warfarin levels may rise

67. Answer Question 4 and 5 Warfarin Aprepitant Interaction Aprepitant is a CYP3A4 substrate, a 3A4 inhibitor and inducer, and a 2C9 inducer. INR may decline. Adapted from Aprepitant Monograph. Retrieved July 22, 2008 from http://www.cancercare.on.ca/pdfdrugs/aprepitant.pdf

68. Importance of Medication Reconciliation Pilot Project of Medication Reconciliation in St. John’s, Newfoundland Cancer Center Summer project Pharmacy Students Obtaining an accurate medication history for chemotherapy patients

69. Total Number of Medications vs. Total Number of Inaccuracies or Omissions Cancer Care Program

70. Identification of the number of patients with inaccuracies or omissions as well as the number of drug related problems identified Cancer Care Program

71. Identification of the number of patients with inaccuracies or omissions as well as the number of patients taking OTC/Herbals Cancer Care Program

72. Starting Docetaxel after FEC M.T. completed her three cycles of FEC as part of the FEC-D regimen. Since the addition of Aprepitant, her nausea control has been much better. Since she is starting Docetaxel, she needs to take Dexamethasone 8 mg po b.i.d. for 3 days, starting 24 hours prior to chemotherapy. The medical oncology team would like to keep M.T. on Aprepitant due to her improved response.

73. Case 1: Question 6 As the oncology pharmacist, you tell the team that they need to be concerned about Aprepitant drug interactions. Which of the following would be correct to tell the team about Aprepitant: A.Aprepitant is a Substrate for CYP3A4,and Moderate Inhibitor of CYP3A4. B. Aprepitant is a Weak Inducer of CYP3A4 and CYP2C9. C. Both A and B are correct.

74. Answer Question 6 - Aprepitant and P450 Substrate for CYP3A4, CYP2C19 and CYP1A2 Weak Inducer of CYP3A4 and CYP2C9 Moderate Inhibitor of CYP3A4 Weak inhibitor of CYP2C9 and CYP2C19

75. Case 1: Question 7 The general recommendations for dosing dexamethasone when combined with Aprepitant is: A. Reduce the dose of dexamethasone by 50% B. Increase the dose of dexamethasone by 50% C. Do not adjust the dose of dexamethasone

76. Answer Question 7 Aprepitant increases the AUC of dexamethasone when the two are administered concomitantly. Reduce dexamethasone dose by 50%.

77. Case 1: Question 8 What would be your recommendations for dosing dexamethasone for Docetaxel premedication when combined with Aprepitant for M.T. : A. Reduce the dose of dexamethasone by 50% B. Increase the dose of dexamethasone by 50% C. Do not adjust the dose of dexamethasone

78. Case 2 Jimmy T. is a A 27 year old with a history of T2N2M1a, Stage III non-seminoma testicular cancer. He had surgery for this and in follow up was found to have metastatic disease. He had at least two lung lesions as well as some mediastinal adenopathy and retroperitoneal adenopathy.

79. Initial Presentation PAST MEDICAL HISTORY: Unremarkable. SOCIAL HISTORY: He lives with his common law girlfriend, Occasional drink on weekends, non smoker MEDICATIONS: Acetaminophen prn SYSTEM INQUIRY: Unremarkable. Allergies : NKA (drugs, food, environmental allergens)a

80. First cycle of chemotherapy (BEP) The patient is prescribed BEP (BLEOMYCIN-ETOPOSIDE- CISPLATIN) Chemotherapy for 4 cycles.

81. Case 2 : Question 1 What anti-emetics would you recommend to be given prior to chemotherapy for his first cycle of BEP? A. A. Metoclopramide 10 mg pre chemotherapy for 5 days B. B. Ondansetron 8 mg, Dexamethasone 8 mg and Aprepitant 125 mg on day 1 pre chemotherapy and Ondansetron 8 mg, Dexamethasone 4 mg and Aprepitant 80 mg on days 2-5 pre chemotherapy C. C. Ondansetron 8 mg and Dexamethasone 8 mg pre chemotherapy on days 1-5

82. Answer Question 1 Multiple Day Chemotherapy A 5-HT3 receptor antagonist should be administered prior to each days 1 st dose of moderately or highly- emetogenic chemotherapy. Dexamethasone should be administered once daily either orally or iv for every day of chemotherapy and for 2-3 days post chemotherapy. Aprepitant may be used for multi-day chemotherapy. Aprepitant 125 mg on day 1, then aprepitant 80 mg daily on days 2 and 3 along with dexamethasone. Based on Phase II data, aprepitant may be safely administered on days 4 and 5 after chemotherapy. Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

83. Case 2: Question 2 The oncology pharmacist performs a toxicity assessment on Jimmy T. 3 days (Monday afternoon) post chemotherapy. The patient complains of significant nausea that started on Sunday evening. He vomited x 1 on Monday morning. He rates the nausea as 8 out of 10. He states he was given a prescription for Ondansetron 8 and Dexamethasone 4 mg po bid x 2 days as well as Metoclopramide 10 mg po q6hprn. The Dexamethasone and Ondansetron were completed on Sunday morning. He did not take the Metoclopramide as he wasn’t sure if he should. What should the oncology pharmacist do for this patient?

84. Answer Question 2 - Breakthrough CINV Management Strategies -Give around the clock administration versus prn. Additional agents should be from a different drug class than initial therapy. No one treatment is better than the other. Possibilities include: metoclopramide, haloperidol, prochlorperazine, cannabinoids, corticosteroids, or agents such as lorazepam. If patient has dyspepsia, consider antacid therapy (H2 blocker or Proton Pump Inhibitor). Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

85. Case 2: Question 3 Which of the following consequence of unresolved CINV do you consider the most important for this patient? A. A. Nutritional depletion and anorexia B. B. Discontinuation of therapy C. C. Esophageal tears

86. Unresolved issues in CINV? Role of risk factor assessment in tailoring antiemetics to the individual at the onset of chemotherapy. Need to develop a better understanding of the pathophysiology of delayed CINV. Increase awareness of CINV for oncology professionals. Newer agents/ formulations Olanzapine New NK-1 antagonists New formulations of 5HT3 antagonists eg transdermal patches, oral sprays, longer acting SC injections

87. Emend Coverage NL Coverage

88. Conclusion Chemotherapy-induced nausea/vomiting (CINV) is a common side effect despite antiemetic therapy. Health care professionals need to ensure patients are being treated according to current antiemetic guidelines. ‘It is always better and easier to PREVENT than to treat nausea/vomiting associated with chemotherapy.’

89. Acknowledgements Katrina Mulherin, Pharm D Student Barbara Wilson, RN, BN, MS, CON(C) Staff (nurses, physicians, pharmacists) at St. John’s Cancer Center