Supportive care session 1:

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1 Board review in oncology pharmacy 2013 Managing Disease or Treatment Related Complication Supportive care session 1: Chemotherapy induced-nausea and vomiting Suthan Chanthawong, B. Pharm, RPh.

2 Objectives Introduction of CINV Risk factors associated with CINV Categories of CINV Pathophysiology of CINV Therapeutic goal Pharmacologic agents indicated for CINV Current guidelines for CINV management

3 CINV prevalence Occurs in up to 80% of patients receiving CMT 1 In a study of 151 cancer patients from 10 community oncology centers who were scheduled for their first cycle of a new CMT regimen, 67% experienced either acute or delayed CINV during their first CMT cycle. 2 Delayed CINV was more common than acute CINV (59% vs 36%), although many patients experienced both types Anticipatory CINV occurs in 18 57% 3 1. Nevidjon B, Chaudry R. Supportive Oncology. 2010;8: Cohen L et al. Support Care Cancer. 2007;15: National Comprehensive Cancer Network. Antiemesis. Clinical Practice Guidelines in Oncology. 2010;

4 Definitions Nausea Retching Vomiting Anticipatory Breakthrough

5 Patients' Rankings of the Top 5 Chemotherapy Complaints Rank 1983 [1] 1993 [3] 1995 [1] 1999 [4] 2004 [2] 1 Vomiting Nausea Nausea Nausea Fatigue 2 Nausea Constantly Hair loss Hair loss Nausea tired 3 Hair loss Hair loss Vomiting Constantly tired Sleep disturbances 4 Thought of treatment 5 Length of treatment Effect on family Constantly tired Vomiting Vomiting Injections Taste changes Weight loss Hair loss de Boer-Dennert M, et al. Br J Cancer. 1997;76: Abstract Hofman M, et al. Cancer. 2004;101: Abstract Sun CC, et al. Support Care Cancer. 2005;13: Abstract Griffin A, et al. Ann Oncol. 1996;7: Abstract Lindley C, et al. Cancer Practice. 1999;7: Abstract

6 Consequences of CINV Medical complications Electrolyte imbalances Dehydration Quality of life Impact daily functioning Compliance with chemotherapy

7 Risk factors Patient Disease Treatment Age <50 years Women > men History of light alcohol use History of vomiting with prior exposure to CMT Other risks History of motion sickness History of nausea or vomiting during pregnancy History of anxiety GIT Partial/complete bowel obstruction, constipation Gastroparesis Tumor or chemotherapy (eg., vincristine) induced Liver metastases Vestibular dysfunction Increase ICP due to brain metastases Metabolic imbalance Psychophysiologic Anxiety, pain CMT Emetic Risk HIGH (Level 4) >90% MODERATE (Level 3) 31-90% LOW (Level 2) 10-30% MINIMAL (level 1) <10% Hesketh PJ. N Engl J Med 2008;358:

8 CMT Emetogenicity level Emetic Risk Antineoplastic Agents Administered Intravenously High Moderate Low Minimal Carmustine Azacitidine Fluorouracil Panitumumab 2-Chlorodeoxyadenosine Cisplatin Alemtuzumab Bortezomib Pemetrexed Bevacizumab Cyclophosphamide >1500 mg/m 2 Dacarbazine Dactinomycin Mechlorethamine Streptozotocin Bendamustine Carboplatin Clofarabine Cyclophosphamide <1500 mg/m 2 Cytarabine >1000 mg/m 2 Daunorubicin* Doxorubicin* Epirubicin* Idarubicin* Ifosfamide Irinotecan Oxaliplatin Cabazitaxel Catumaxomab Cytarabine <1000 mg/m 2 Docetaxel Doxorubicin HCL liposome injection Etoposide Gemcitabine Ixabepilone Methotrexate Mitomycin Mitoxantrone Paclitaxel Temsirolimus Topotecan Trastuzumab Bleomycin Busulfan Cetuximab Fludarabine Pralatrexate Rituximab Vinblastine Vincristine Vinorelbine *These anthracyclines, when combined with cyclophosphamide, are now designated as high emetic risk Basch E, et al. J Clin Oncol. 2011;29:

9 Categories of CINV Refractory/Intractable Breakthrough Anticipatory Acute Delayed Chemo hours hours Lohr L. J Hematol Oncol Pharm. 2011;1(4):13-21.

10 Pathophysiology Motion Labyrinth disorders Drugs Metabolic products Bacterial toxins ACh H 1 Vestibular System Vestibular nuclei projections Chemoreceptor Trigger Zone Sensory input Anxiety Increased ICP Cortex Intracerebral projections Mechanical stretch GI mucosal injury Local toxins JAMA 2007;298(10): D 2 5HT 3 NK 1 5HT 3 Chemoreceptors Peripheral Pathways Vagus and splanchnic nerves Vomiting Center ACh H 1 5HT 3

11 Neurotransmitter involvements Delayed Acute 5-HT 3 Other factors

12 Neurotransmitter involvements

13 Therapeutic Goal Prevention/ Minimization

14 Pharmacotherapy Aprepitant, March 2003 Palonosetron July, 2003

15 Classes of Antiemetic Agents Serotonin Antagonists Corticosteroids NK 1 Receptor Antagonist (i.e. Aprepitant) Dopamine antagonists Metoclopramide Phenothiazines (i.e. Prochloroperazine) Butyrophenones (i.e. Haloperidol) Benzodiazepines Cannabinoids Olanzapine

16 5HT 3 RA: Practice Pearls Standard therapy for MEC-HEC due to efficacy and low ADRs Addition of corticosteroids is synergistic (20% in effectiveness) Not as effective as corticosteroids for delayed N/V All agents, when administered in equipotent doses, have similar efficacy and safety Palonosetron has longer half-life and more avid receptor binding Granisetron is a patch formulation Current guidelines indicate that PO administration is equivalent to IV administration in efficacy Basch E, et al. J Clin Oncol. 2011;29: Antiemetic Subcommittee of the MASCC. Ann Oncol 2010;21 (Suppl 5):v232-v243. NCCN Guidelines Version Antiemesis. National Comprehensive Cancer Network.

17 5HT 3 RA: Adverse effects Headache Constipation or diarrhea Transient ECG interval abnormalities (QT prolongation), often asymptomatic Somnolence, sedation Elevated transaminases, dizziness

18 5HT 3 RA: FDA Warning!!! September 2011, FDA released an alert concerning an association between Zofran (ondansetron) and prolongation of QT intervals. The FDA required a revision of labeling as follows: to include a warning to avoid use in patients with congenital long QT syndrome.additionally, recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), CHF, bradyarrhythmias, or in patients taking other medications that can lead to QT prolongation U.S. Food and Drug Administration. September 15, 2011.

19 5HT 3 RA: FDA Warning!!! A subsequent report the FDA made the following recommendations: A recently completed clinical study suggests that a 32mg single IV dose of ondansetron may affect the electrical activity of the heart (QT interval prolongation), which could predispose patients to develop Torsades de Pointes. Ondansetron will continue to be used in the prevention and treatment of CINV; HOWEVER, no single IV ondansetron dose should exceed 16mg. This does not change any of the recommended oral dosing regimens for ondansetron (max PO dose = 24mg). U.S. Food and Drug Administration. June 29, 2012.

20 Corticosteroids Dosing: Dexamethasone dose ranges from 8-20mg Methylprednisolone dose ranges from mg Reduce dose when used with aprepitant/fosaprepitant Do not give additional steroid if present in treatment regimen Basch E, et al. J Clin Oncol. 2011;29: Antiemetic Subcommittee of the MASCC. Ann Oncol 2010;21 (Suppl 5):v232-v243. NCCN Guidelines Version Antiemesis. National Comprehensive Cancer Network.

21 Corticosteroids: Adverse effects Adverse effects may include: Euphoria, anxiety, insomnia Increased appetite Hyperglycemia Mild fluid retention When IV doses are given too rapidly patient may experience transient and intense perianal, vaginal, or anal burning Basch E, et al. J Clin Oncol. 2011;29: Antiemetic Subcommittee of the MASCC. Ann Oncol 2010;21 (Suppl 5):v232-v243. NCCN Guidelines Version Antiemesis. National Comprehensive Cancer Network.

22 NK 1 RA: Practice Pearls Augments the antiemetic activity of 5-HT 3 RA and corticosteroids to inhibit acute and delayed phases of CINV in both MEC-HEC Do not use as single agent Adverse effects: Fatigue, Hiccups, Weakness, dizziness Basch E, et al. J Clin Oncol. 2011;29: Antiemetic Subcommittee of the MASCC. Ann Oncol 2010;21 (Suppl 5):v232-v243. NCCN Guidelines Version Antiemesis. National Comprehensive Cancer Network.

23 NK 1 RA: Practice Pearls Aprepitant A substrate, a moderate inhibitor An inducer of CYP3A4 when used as a 3-day regimen Fosaprepitant Given as a single dose Weak inhibitor of CYP3A4 (does not induce CYP3A4) Basch E, et al. J Clin Oncol. 2011;29: Antiemetic Subcommittee of the MASCC. Ann Oncol 2010;21 (Suppl 5):v232-v243. NCCN Guidelines Version Antiemesis. National Comprehensive Cancer Network.

24 Merck & Co., Inc. Product Information Chemotherapy induced nausea and vomiting (CINV) NK 1 RA: Drug-Drug interactions Potential drug interactions include: Oral contraceptives (decreased efficacy) Warfarin (decreased efficacy) Dexamethasone/methylprednisolone (increased efficacy) Midazolam (increased efficacy) CYP3A4 inhibitors (increase aprepitant AUC) Erythromycin, itraconazole, ketoconazole, etc CYP3A4 inducers (decrease aprepitant AUC) Carbamazepine, phenytoin, rifampin

25 NK 1 RA: CMT Drug interactions CMT known to be metabolized by CYP3A4: Docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine Doses were not adjusted when used concurrently with etoposide, vinorelbine, or paclitaxel in phase III trials, but caution is warranted Ifosfamide neurotoxicity Recent study found no association between aprepitant use and the risk of neurotoxicity in patients receiving ifosfamide-based therapy; caution is warranted Jarkowski,A., et al. The Oncology Pharmacist; April Product Information. Merck & Co.

26 NK 1 RA: Dosage regimens ORAL Aprepitant 125mg PO day 1, 80mg PO days 2 and HT 3 of choice day 1 Dexamethasone 12mg PO day 1, 8mg PO days 2, 3, 4 IV Fosaprepitant 150mg IV day 1 (only) 5-HT 3 of choice day 1 Dexamethasone 12mg PO day 1, 8mg PO day 2, 8mg PO BID days 3 and 4 Jarkowski,A., et al. The Oncology Pharmacist; April Product Information. Merck & Co.

27 NK 1 RA: Administration Final concentration: 1mg/ml in NSS Infusion > minutes using PVC-free tubing; increase administration time and/or solution volume if phlebitis develops Incompatible with divalent cations (Mg, Ca) infuse through NNS line only Incompatible with palonosetron flush pre/post with NSS Compatible (admix or Y-site) with ondansetron or granisetron and dexamethasone or methylprednisolone May cause hypersensitivity reactions (contains the same base as contained in docetaxel) Jarkowski,A., et al. The Oncology Pharmacist; April Product Information. Merck & Co.

28 D 2 RA: Phenothiazines Effective with LEC-MEC; delayed N/V Prochlorperazine 10mg PO/IV/IM Q6hr (max of 40mg/day); 25mg Suppo PR Q12hr Promethazine Not a very potent antiemetic for cancer patients IV use mg PO every 4 hours 25mg PO Phenergan ~ = 6.25mg IV Q4-6hr Strong vein irritant; give IV via central line Jarkowski,A., et al. The Oncology Pharmacist; April Product Information. Merck & Co.

29 D 2 RA: Phenothiazines Adverse effects (class) Sedation (especially with IV and in elderly) Hypotension Akathisia and dystonia Jarkowski,A., et al. The Oncology Pharmacist; April Product Information. Merck & Co.

30 D 2 RA: Others Metoclopramide D 2 antagonist at lower doses; 5HT 3 RA at high doses Use in breakthrough N/V Dosing: 10-20mg PO/IV Q6hr PRN Most common ADRs diarrhea, dystonia, EPS Haloperidol Used in breakthrough N/V Dosing: 0.5-1mg PO/IV/IM Q6hr PRN Most common ADRs drowsiness, dystonia, dry mouth, EPS Jarkowski,A., et al. The Oncology Pharmacist; April Product Information. Merck & Co.

31 Benzodiazepines Antianxiety agents: Treated ANV or breakthrough CINV They may delay the onset of ANV and help to control sleep disturbances related to diagnosis and chemotherapy Affect the limbic system and cortical input into the medulla Agents commonly recommended: Lorazepam Alprazolam Adverse effects Sedation, dizziness, amnesia, respiratory depression Lohr,L. The Cancer Journal 2008;14(2):85-93.

32 Select Antiemetics for CINV Drug Dose Indication NK 1 RA: Aprepitant/ fosaprepitant 5HT 3 RA: Dolasetron Granisetron Ondansetron Palonosetron ACUTE : 125 mg PO or 115 mg IV DELAYED : 80 mg PO daily x 2 days ACUTE: 100 mg-200 mg PO or 100 mg IV DELAYED: 100 mg PO/IV daily CINV ACUTE: 1 mg-2 mg PO or 1 mg IV or GTDS 3.1 mg/24 hrs DELAYED: 2 mg PO daily or 1 mg PO twice daily (no further dosing with GTDS) ACUTE: 8 mg-24 mg PO or 8 mg-24 mg IV DELAYED: 8 mg PO twice daily or 16 mg PO daily or 8 mg IV twice daily ACUTE: 0.5 mg PO or 0.25 mg IV DELAYED: not recommended (single dose only) Prophylaxis of acute & delayedcinv (with 5HT 3 RA + dexamethasone) Prophylaxis of acute & delayed See above See above See above

33 Select Antiemetics for CINV Drug Dose Indication Benzodiazepines: Alprazolam Lorazepam Corticosteroids: Dexamethasone Dopamine RA: Prochlorperazine Promethazine 0.5 mg-2 mg PO Q 6H 0.5 mg-2 mg PO/IV/Sublingual Q 6H ACUTE : 10 mg-20 mg PO/IV (with aprepitant 12 mg PO/IV) DELAYED: 4 mg-8 mg PO/IV twice daily 10 mg PO/IV Q 6H (may dose Q 4H) 25 mg PR Q 6H 12.5 mg-25 mg PO/IV Q 6H (may dose Q 4H) 25 mg PR Q 6H 6.25 mg/0.1 ml in PLO gel topically Q 4H Anticipatory CINV (drug class of choice) Prophylaxis of acute & delayed CINV (with aprepitant 8 mg PO daily) Treatment of breakthrough CINV; prophylaxis for acute & delayed CINV (with low-risk agents) See above Metoclopramide Droperidol Haloperidol Standard dose: 10 mg-40 mg PO/IV Q 6H (may dose Q 4H) High dose: 0.5 mg/kg-2 mg/kg IV with diphenhydramine 25 mg IV Q 4H mg-1.25 mg IV Q 6H 1 mg IV Q 6H Treatment of breakthrough CINV; prophylaxis of acute (high-dose only) & delayed (with steroids) CINV Treatment of breakthrough CINV See above

34 Practice Guidelines NCCN (National Comprehensive Cancer Network) Revised several times each year Antiemesis pocket Version ASCO (American Society of Clinical Oncology) Updated periodically with most recent in MASCC (Multinational Association of Supportive Care in Cancer) 9 oncology organizations from around the world Most recent update 2011 Other contributors: Oncology Nursing Society (ONS) American Society of Health-System Pharmacists (ASHP)

35 Rule(s) of Thumb Combination therapy: More emetogenic Multiday regimens: At risk for both acute and delayed N/V Emetogenicity is dose-related Emetogenic potential: Different on different days of treatment Antiemetic choices: Based on highest level of emetogenicity

36 Recommendation Professional society ASCO 1 HEC 3-drug combination: NK 1 RA: days HT 3 RA + Dexamethasone: days 1-4 MEC 2-drug combination: Palonosetron + Dexamethasone Preferred If palonosetron is not available, any firstgeneration 5-HT 3 RA, preferably granisetron or ondansetron Evidence on adding aprepitant is limited, but clinicians may consider use of the agent HEC: High-emetic-risk chemotherapy, MEC: Moderate-emetic-risk chemotherapy regimens AC indicates anthracycline plus cyclophosphamide; ASCO, American Society of Clinical Oncology Basch E, et al. J Clin Oncol 2011;29:

37 Recommendation Professional society NCCN 1 HEC Acute and delayed prevention: Prevention: MEC 5-HT 3 RA on day 1 (palonosetron is preferred) + Steroid b on days NK 1 RA on days 1-3 Data for post-cisplatin ( 50 mg/m 2 ) emesis prevention are cat1; others are cat 2A Begin day 1: 5-HT 3 RA (all are cat 1; palonosetron, on day 1 only, is preferred a ) + Steroid b +/- NK 1 RA Days 2 and 3: 5-HT 3 RA (dola, grani,or ondansetron) Or Steroid monotherapy b Or NK 1 RA +/- steroid (if NK 1 antagonist is used on day 1) c HEC: High-emetic-risk chemotherapy, MEC: Moderate-emetic-risk chemotherapy regimens AC indicates anthracycline plus cyclophosphamide, NCCN, National Comprehensive Cancer Network.

38 Recommendation Professional society HEC MASCC/ESMO 1 Acute prevention: 5-HT 3 RA + Dexamethasone, + Aprepitant MEC Acute prevention for AC regimens: 5-HT 3 RA + Dexamethasone + Aprepitant Delayed prevention: Dexamethasone + Aprepitant Delayed prevention (other than AC): Dexamethasone Delayed prevention for AC regimens: Aprepitant HEC: High-emetic-risk chemotherapy, MEC: Moderate-emetic-risk chemotherapy regimens AC indicates anthracycline plus cyclophosphamide; MASCC/ESMO, Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology

39 Conceptual Frame Work: ASCO Regimen: AC Palonosetron: preferred

40 Case Study: Jung Beoi (JB) JB is a 49-year old woman who was recently diagnosed with extensive stage SCLC. She is a non-drinker who stopped smoking 10 years ago. Her PMH is significant for anxiety and motion sickness. Her physician plans to start PE regimen every 28 days to treat her disease. Cisplatin 75mg/m 2 (day 1) Etoposide 100mg/m 2 (days 1-3)

41 Point to consider 1. What is the emetogenic potential of the chemotherapy prescribed for JB? 2. What are the risk factors associated with the development of CINV?

42 Case Study: Jung Beoi JB is a 49-year old woman who was recently diagnosed with extensive stage SCLC. She is a non-drinker who stopped smoking 10 years ago. Her PMH is significant for anxiety and motion sickness. Her physician plans to start PE regimen every 28 days to treat her disease. Cisplatin 75mg/m 2 (day 1) HEC (day 1) Etoposide 100mg/m 2 (days 1-3) LEC (day 1-3)

43 Point to consider 3. What is the rationale for the anti-emetic therapy prescribed in this case? 4. Why are these drugs prescribed in combination?

44 Case Study: Jung Beoi Treatment risk: Cisplatin (day 1) HEC Etoposide (days 1-3) LEC Emetic Pattern: HIGH Risk = 3 days after last dose of CMT MODERATE Risk = 2 days after last dose of CMT LOW Risk = 1 day after last dose of CMT +/- PRN Patient should be protected throughout the full period of risk

45 Case Study: Jung Beoi The FDA recommends a maximum of 16 mg for a single dose of IV ondansetron, PO 24 mg

46 Case Study: Jung Beoi Prophylaxis regimen: 5-HT 3 + NK 1 + corticosteroid* Palonosetron 0.25mg IV day 1 + Dexamethasone 20mg PO/IV day 1, 8mg PO Q12hr day 2-4 Prochlorperazine 10mg PO Q6hr PRN: breakthrough N/V

47 Case Study: Jung Beoi Presents to clinic 5 days after her first cycle of cisplatin and etoposide. She states that she had continuous nausea with several episodes of emesis and is considering no further therapy. She has been using prochlorperazine without significant benefit.

48 Breakthrough: Consideration In case of has no N/V don t change anything In case of has N/V: choose an agent with a different mechanism of action and add PRN to current regimen Take patient-specific characteristics into consideration Anxiety, depression, concurrent medications, dyspepsia Multiple concurrent medications may be required If N/V controlled: continue breakthrough medication(s) on scheduled basis

49 Breakthrough: Consideration If N/V uncontrolled: Consider changing antiemetic therapy to higher-level primary treatment Consider adding aprepitant/fosaprepitant Add other antiemetics, such a dopamine antagonists, butyrophenones Adjust intensity or frequency of 5-HT 3 Changing to a different 5-HT 3 may be of questionable benefit If treatment goal is non-curative, consider different chemotherapy regimen Adding an anxiolytic to combination antiemetics Consider antacid, H 2 antagonist or PPI therapy in patients with dyspepsia

50 Breakthrough: Consideration

51 Breakthrough: JB management Addition of metoclopramide is a very reasonable choice 10-20mg PO Q6hr If she responds favorably, this should be added as a scheduled med to her regimen with the next cycle. If not, consider haloperidol, olanzapine or cannabinoids Others possible: Gabapentin Antihistamine

52 Breakthrough CINV: Olanzapine Inhibit D 2, 5HT, ACh and H 1 receptors Adverse effects: Sedation or sleep disturbance Fatigue, dizziness Dry mouth Weight gain Cautions: Use in elderly Hyperglycemia; an association with onset of DM QT prolongation

53 Olanzapine: Standard prevention Compared with aprepitant-based regimens in MEC-HEC as standard prevention regimen Result: Effective as in acute N/V control More effective in controlling delayed symptoms Dosing: mg/day starting day (HS) before or day of chemotherapy and continue for 5-10 days Navari,RM., et al. J Support Oncol 2011;9:

54 Breakthrough CINV: Olanzapine Chanthawong S, et al. J Clin Oncol 2011;29(suppl; abstract e19596).

55 Breakthrough CINV: Olanzapine Phase II prospective open label (Sep 2009 Jul 2010) Sample: 46 solid tumors patients with HEC Intervention: Olanzapine 5 mg orally every 12 hours (2 doses) in patients experiencing breakthrough emesis Monitoring: evaluated every 6 hours for 24 hours Results: Major respond of 78.2% (CR of 60.8%, PR 17.4%) ADRs: mild including dizziness, fatigue and dyspepsia Chanthawong S, et al. J Clin Oncol 2011;29(suppl; abstract e19596).

56 Refractory CINV Patients with persistent N/V after CMT should be evaluated for other possible causes: Brain metastases Electrolyte abnormalities Tumor infiltration of bowel or other GI abnormalities Other comorbidities

57 Case Study: Jung Beoi 6. What are the options for CINV prophylaxis for JB s next cycle of chemotherapy?

58 Standard prevention: Plan Prophylaxis regimen: 5-HT 3 + NK 1 + corticosteroid* Palonosetron 0.25mg IV day 1 + Aprepitant 120mg PO day 1, 80mg PO day 2,3 + Dexamethasone 12mg PO/IV day 1, 8mg PO day 2-4 Olanzapine 5mg PO Q 12 hr PRN: breakthrough N/V Lorazepam 0.5mg PO hs: Anticipatory N/V

59 Anticipatory CINV: Risk factors Age < 50 years N/V after last CMT administration Feeling warm or hot all over after last CMT administration Susceptibility to motion sickness History of anxiety or depression Experiencing sweating and/or generalized weakness after last CMT administration Aapro, MS., et al. Support Care Cancer 2005;13:

60 Anticipatory CINV: Risk factors

61 Take home messages Evaluate each patient individually Evaluate the emetogenic potential and pattern of the chemotherapeutic regimen to be given Antiemetics are most effective when given prophylactically Flexibility is the key

62 Thank you for your attention!