9/21/2016. Disclosures. Updates in the Management of Chemotherapy induced Nausea and Vomiting (CINV) Introduction. Objectives.

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1 Updates in the Management of Chemotherapy induced Nausea and Vomiting (CINV) Diwura Owolabi, Pharm.D, BCOP Clinical Pharmacy Specialist, Blood and Marrow Transplantation Methodist University Hospital, Memphis Disclosures No disclosures or conflict of interest Objectives Review recently approved drugs in the management of CINV Discuss select recent landmark trials for new drugs in the management of CINV Summarize key updates to evidence and practice based guidelines on the management of CINV Introduction One of the top feared and distressing side effect of chemotherapy 70% 80% of all patients receiving chemotherapy without appropriate prophylaxis will develop CINV Even with prophylaxis, up to 35 % of patients will develop acute CINV & ~54 % develop delayed CINV Boccia et al. JCOM. 2013;20,8: Grunberg SM et al. Cancer :15;100(10): Impact of CINV Medical complications Dehydration, electrolyte imbalances, hospitalization Poor nutrition, weight loss Disruption, delay or noncompliance to chemotherapy Decline in performance status and mental status Impaired quality of life and physical well being Definitions Acute CINV Occurs within the first 24hrs of chemotherapy Delayed CINV Occurs 24hrs after chemotherapy and lasts up to 7 days Anticipatory CINV Occurs before chemotherapy administration, usually triggered by sight, sound or smell Due to poor control of CINV in previous cycles Breakthrough CINV Occurs despite adequate/appropriate prophylaxis, often needing rescue medications Boccia et al. JCOM. 2013;20,8:

2 Pathophysiology Risk factors Patient Specific Age (younger > older) Gender (women > men) Low alcohol consumption Emesis with prior chemo History of motion sickness or morning sickness Psychosocial factors : anxiety, depression, distress Treatment Specific Emetic risk category of chemotherapy regimen Chemotherapy dose Chemotherapy schedule combination & rate Chemotherapy in combination with radiation Overall emetic risk = Patient risk factors + regimen risk factors Chemotherapy Emetic Risk Category Category Emetic Risk Examples High (HEC) Risk in nearly all patients Cisplatin, cyclophosphamide (>90%) >1500mg/m 2, doxorubicin>60mg/m 2 Moderate (MEC) Risk in 30% to 90% of patients Carboplatin, oxaliplatin, busulfan, melphalan, irinotecan, idarubicin Low Risk in 10% to 30% of patients Docetaxel, etoposide, 5 FU, gemcitabine, paclitaxel, topotecan Minimal Fewer than 10% at risk Bortezomib, decitabine, nivolumab, bleomycin, bevacizumab HEC: High emetic risk category MEC: Moderate emetic risk category Agents used in CINV Neurokinin receptor antagonists Aprepitant, fosaprepitant 5HT 3 receptor antagonists Palonosetron, ondansetron, granisetron, dolasetron Corticosteroids Dexamethasone Dopamine antagonists Metoclopramide, promethazine, prochlorperazine, haloperidol Others Lorazepam, dronabinol, diphenhydramine, scopolamine Poll Question 1. Which of the following drugs were recently approved by the FDA for the prevention and/or treatment of CINV? A. Varubi (Rolapitant) B. Sustol (Granisetron ER) C. Syndros (Dronabinol solution) D. All of the above E. A & B only What s New? Granisetron (Sancuso ) 2008 Fosaprepitant (Emend ) 2008 Aprepitant (Emend ) 2003 Palonosetron (Aloxi ) 2003 Dolasetron (Anzemet ) 1997 Granisetron (Kytril ) 1994 Ondansetron (Zofran ) 1991 Netupitant/Palonosetron (NEPA) Akynzeo Ondansetron Zuplenz Rolapitant Varubi 2015 Olanzapine Zyprexa Dronabinol Syndros 2016 Granisetron Sustol

3 Ondansetron Oral Film (Zuplenz ) Ondansetron oral soluble film Rapidly dissolves in mouth in 10 secs Pleasant peppermint flavor with no gritty aftertaste Eliminates the burden of swallowing pills Clinically bioequivalent to ondansetron orally disintegrating tablets (ODT) Same efficacy and side effect profile Available in same doses as zofran : 4mg, 8mg Data on File, Midatech Pharma US Inc. Netupitant/Palonosetron (Akynzeo ) Oral single dose fixed combination of netupitant (300 mg) and palonosetron (0.50 mg) Netupitant Novel highly selective NK 1 receptor antagonist (RA) High brain penetration Long half life of ~90hrs vs aprepitant ~9 13 hrs Palonosetron Second generation 5HT 3 RA Long half life of ~40 hrs Janicki PK. Ther Clin Risk Manag :2;12:693 9 Netupitant/Palonosetron (NEPA) NEPA Clinical Trials PALO: Palonosetron APR: Aprepitant : dexamethasone NEPA synergistically prevents the NK 1 receptor response against substance P Additive effect on NK 1 receptor internalization Substrate and moderate inhibitor of CYP3A4 Dose adjustments when given with other CY3A4 substrates (dexamethasone) No interactions with CYP2C9 substrates and chemotherapy agents that are CYP3A4 substrates Aapro et al ( n=1455) superiority trial MEC (AC) Gralla et al (n=413) Randomized 3:1 HEC (76%) MEC (24%) D1: NEPA + (n=308) D1: NEPA + D2 4: D1: PALO + (No NK1) (n=104) D1: APR + PALO + D2 3: APR + D4: CR (No emesis, rescue medications) Acute (0 24hrs): 88.4% vs 85% (p=0.047) Delayed (25 120hr): 76.9% vs 69.5% (p=0.001) Overall (0 120hr): 74.3% vs 66.6% (p=0.001) Primary endpoint: Safety after multiple cycles Treatment related ADEs 16 (5.2%) vs 3 (2.9%) CR (No emesis, rescue medications) Cycle 1: Overall (0 120hr): 81% vs 76% Cycle 2: Overall (0 120hr): 86% vs 81% Cycle 3: Overall (0 120hr): 91% vs 87% Cycle 4: Overall (0 120hr): 90% vs 88% Hesketh PJ et al Biomed Res Int. 2015; 2015: Aapro M et al Ann Oncol. 2014;25(7): Gralla et al. Ann Oncol ; 25(7): Safety Profile of NEPA Comparable safety profile to aprepitant/palonosetron Most common treatment related ADEs Constipation (3.6%) Headaches (1%) Cardiac adverse effects Most frequent ECG change was flat T waves (17%) and ST depression (12%) Few treatment related ADEs and discontinuations Rolapitant (Varubi ) Novel highly selective long acting oral NK 1 RA Long half life of ~180 hours NK 1 receptor occupancy >90% in cortex and 73% in striatum 5 days after single oral dose Oral single dose of 180mg ( two 90mg) Given 1 2 hours before chemotherapy NDA application submitted for intravenous (IV) formulation Gralla et al. Ann Oncol ; 25(7):

4 Rolapitant (Varubi ) Rolapitant Clinical Trials ROLA: Rolapitant GRA: Granisetron APR: Aprepitant, : dexamethasone Does not induce/ inhibit CYP3A4 but inhibits CYP2D6 No dose adjustments required with dexamethasone or other drugs metabolized CYP3A4 Contraindicated in patients receiving thioridazine, a CYP2D6 substrate. QT prolongation and Torsades de Pointes Avoid other CYP2D6 substrates with narrow therapeutic index Inhibitory effect on CYP2D6 lasts for at least 7 days Rapoport BL et al 2 HEC1 (n= 532) HEC2 (n=555) Schwartzberg LS et al. (n=1369) MEC or AC D1: ROLA 180mg + GRA 10μg/kg IV + D2 3: ROLA 180mg + GRA 2mg + D1: Placebo + GRA 10μg/kg IV + D2 3: (No NK1) Placebo + GRA 2mg + CR (No emesis, no rescue antiemetic) HEC 1: 73% vs 58%; OR 1 9, p= HEC 2: 70% vs 62%; OR 1 4, p= Pooled studies: 71% vs 60%; OR, p= CR (No emesis, no rescue antiemetic) in delayed phase (>24 120h) Delayed phase:: 71% vs 62%, p = Overall phase : 69% vs 58%, p = Acute phase (83% vs 80%; p = 0.14) No difference in acute phase Rapoport BL et al. Lancet Oncol. 2015;16(9): Schwartzberg LS et al. Lancet Oncol. 2015;16(9): Safety Profile of Rolapitant Safety profile comparable to other NK 1 RA Few treatment related ADEs and discontinuations Do not administer at less than 2 week interval Avoid CYP2D6 substrates (pimozide, thioridazine) Most common treatment related ADEs Constipation, headaches, hiccups, dyspepsia Lorusso V. Ther Clin Risk Manag. 2016; 12: Dronabinol Oral Solution (Syndros ) Liquid version of Marinol (dronabinol) soft gel capsules Flexible administration option Allows for rapid absorption Easy titration to clinical effects Lower intra patient variability Active ingredient tetrahydrocannabinol (THC) Available as 5mg/ml solution Recommended starting dose is 4.2mg/m hours prior to chemo, then every 2 4 hours after for a total of 4 to 6 doses per day. Dronabinol Oral Solution (Syndros ) Approved for CINV in patients who have failed conventional antiemetic treatments Also approved for anorexia associated with weight loss in patients with AIDS Approval based on bioequivalence/pharmacokinetics compared with marinol Parikh N et al. J Clin Oncol. 2016; 34(suppl; abstr e21595) Syndros. Insys Therapeutics, Inc., Chandler, AZ Parikh N et al. J Clin Oncol. 2016; 34(suppl; abstr e21595) 4

5 Safety Profile of Syndros Similar safety profile with marinol Warnings/precautions: Psychiatric and cognitive effects which may impair mental and/or physical abilities Hypotension, hypertension, syncope, or tachycardia in patients with cardiac disorders Interaction with disulfiram and metronidazole Hold products with disulfiram or metronidazole at least 14 days before administration and 7 days after treatment Seizures in patient with seizure history Syndros. Insys Therapeutics, Inc., Chandler, AZ Granisetron ER (Sustol ) Novel extended release subcutaneous granisetron Biochronomer polymer based delivery system providing therapeutic concentrations for 5 days Contains 2% granisetron and a polymer vehicle Controlled hydrolysis resulting to slow controlled and sustained release of drug Available as a 10mg/0.4ml single dose prefilled syringes At least 30 minutes before chemotherapy on days 1 Raftopoulos H et al. Support Care Cancer 2015;23: Granisetron ER (Sustol ) Sustol Clinical Trials PALO: Palonosetron FOSP: Fosaprepitant : dexamethasone Administration by health care provider only Administer in upper arm of skin or abdomen Requires slow sustained injection due to high viscosity Do not give more frequently than once every 7 days Renal Adjustments: Moderate (Clcr 30 59ml/min): Give every 14 days Severe (Clcr <30ml/min): Do not use Raftopoulos H et al MEC(n= 669) HEC (n=735) Schnadig I et al (MAGIC) (n=942) HEC D1: APF350 5mg or APF350 10mg + D2 3: D1: APF350 10mg + D2 4: D1: PALO 0.25mg + D2 3: D1: Zofran + FOSP+ D2 4: Noninferiority to palonosetron during acute and superiority during delayed phase (CR) Acute CR (MEC): 74.8%,76.9% vs 75% [ 9.8,9.3] Acute CR (HEC): 77.7%,81.3% vs 80.7%[ 7.7,8.7] Delayed MEC: 58.5% vs 57.2% [ 9.5,12.1] APF350 was not superior to palonosetron during delayed phase but noninferior CR (No emesis, no rescue antiemetic) in delayed phase (>24 120h) Delayed phase:: 64.7% vs 56.6%, p = Overall phase : 58.4% vs 52.9%, p = Acute phase (75% vs 73%; p =.502) No difference in acute phase Raftopoulos H et al. Support Care Cancer 2015;23: Schnadig I et al Future Oncol.2016;12: Safety Profile of Sustol Similar safety profile with other 5HT 3 antagonist Warnings/precautions: Injection site reactions (IRS) Can occur 2 weeks or more after administration Increased risk of bruising /hematomas with anticoagulants and antiplatelet Gastrointestinal: constipation, decreased bowel activity Most common adverse reactions ( 3%) IRS, constipation, fatigue, headache, diarrhea, abdominal pain, insomnia Olanzapine (Zyprexa ) Atypical antipsychotic Second generation thienobenodiazepine Initially approved in 1996 for psychotic disorders Not FDA approved for CINV Attractive drug as it targets many receptors Dopaminergic (D1, D2, D3, D4), serotonergic (5 HT2A, 5 HT2C, 5 HT3, 5 HT6), adrenergic, histaminergic (H1), and muscarinic (m1, m2, m3, m4) receptors. DeRemer D et al. Pharmacotherapy ;36(2):

6 Pathophysiology Olanzapine Clinical Trials OLP: Olanzapine PALO: Palonosetron APR: Aprepitant, : dexamethasone DeRemer D et al. Pharmacotherapy ;36(2): Tan L et al 2009 (n=229) HEC (n=102) MEC (n=127) Shumway NM et al 2009 (n=18) HEC D1: Azasetron + 10mg + OLP 10mg D2 5: OLP 10mg Olanzapine: D 2, 1: OLP 5mg D1: OLP 10mg + PALO + D2 4: OLP 5mg + D1: Azasetron + 10mg D2 5: 10mg Aprepitant: D 2, 1: Placebo D1: APR + PALO + D2 3: APR + D4: Placebo + CR for delayed Nausea (%) (p<0.05) HEC: 69.6 vs 30.4( 39%) MEC: 83 vs 58( 25%) CR for delayed Vomiting (%) (p<0.05) HEC: 78.6 vs 56.5( 22%) MEC: 89 vs 76( 13%) No difference seen in acute nausea & vomiting responses CR (No emesis or rescue antiemetic ) Anticipatory: 87.5% (OLP) vs 77.8% (APR) Acute: 75% (OLP) vs 44 % (APR) Delayed: 62.5% (OLP) vs 55.6% (APR) Tan L et al. J Exp Clin Cancer Res. 2009; 28(1): 131 Shumway et al. J Clin Oncol 2009;27:9633 Olanzapine Clinical Trials Navari et al 2011 (n=247) HEC Navari et al 2016 (n=380) HEC OPD: D1: OLP 10mg + PALO + D2 4: OLP 10mg D1: OLP 10mg + 5HT3 + + NK1 D2 4: OLP 10mg + APD: D1: Aprepitant + PALO + D2 3: APR + D4: Placebo + D1: Placebo + 5HT3 + + NK1 D2 4: Placebo + OLP: Olanzapine PALO: Palonosetron APR: Aprepitant, : dexamethasone CR (No emesis, no rescue antiemetic) p >0.05 Day 1: 97% (OPD) vs 87% (APD) Days 2 5: 77% (OPD) vs 73% (APD) Overall: 77% (OPD) vs 73% (APD) Patients without Nausea: OPD: 87% acute, 69% delayed, overall 69% APD: 87% acute, 38% delayed, overall 38% Primary endpoint (No nausea after chemo) 24hrs : 74% (OLP) vs 45% (P) p< hrs: 42 % vs 25 % p= hrs: 37% vs 22% p=0.002 CR (No emesis, no rescue antiemetics) 24hrs (86% vs 65%) hrs (67 % vs 52%) 0 120hrs( 64% vs 41%) p <0.001 Olanzapine Dosing Several doses and duration have been studied Standard dosing : 10mg daily (max=20mg/day) Lower doses (5mg) may be used for select patients No loading dose, start days 1 to days 3/4 of chemotherapy Effective in treating breakthrough CINV 10mg daily for 3 days Best olanzapine containing regimen? Quadruple regimen (OLP +NK 1 + 5HT 3 + ) Triple regimen ( Substitute OLP for NK 1 or 5HT 3 ) Navari NM et al. J Support Oncol ;9(5): Navari NM et al N Engl J Med 2016;375: Safety Profile of Olanzapine Price Comparison of New Agents Good safety profile No grade 3 or 4 adverse drug reactions in studies Most common adverse effects Fatigue, sedation, drowsiness, somnolence, disturbed sleep, sedation, increased appetite, weight gain Use with caution in special populations Elderly patients Concurrent medications that depress CNS (lorazepam) Agent Ondansetron oral film (Zuplenz) Dronabinol solution (Syndros) Netupitant/Palonosetron (NEPA) Rolapitant (Varubi) Olanzapine (Zyprexa) Granisetron (Sustol) AWP Package Price ~$32/dose ( 1 oral film) Not available $659/dose (1 tablet) $636/dose ( 2 tablets) ~$20/tablet $594/dose Redbook Online [online database]. Greenwood Village, CO: Truven Health Analytics 6

7 Poll Question 1. Which of the following statements are false? A. Dose reductions are necessary when administering rolapitant with other CYP3A4 substrates B. Olanzapine was recently FDA approved for the prevention of CINV C. Patient may inject self with Sustol before presenting to clinic for day 1 of chemotherapy D. Renal dose adjustments are not necessary for Sustol E. All of the above CINV Guidelines Evidence based guidelines MASCC/ESMO: Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology ASCO: American Society of Clinical Oncology Practice based guidelines NCCN: The National Comprehensive Cancer Network CINV Guidelines Expert Panel Select ASCO members ASCO MASCC/ESMO NCCN Select members across several countries/continents Select members from NCCN member institutions Last Updated Nov 2015 March 2016 April 2016 Methodology Evidence based Evidence based Consensus based United States Multinational 5 continents 15 countries United States Are We Adhering to Clinical Guidelines? Adherence to clinical guidelines nationwide low Aapro et al showed guideline adherence of only 29% in a large European observational study (n=1000) INSPIRE trial by Gilmore et al also showed adherence to NCCN guidelines very low in US Highly emetogenic chemotherapy (HEC) : 29% Moderate emetogenic chemotherapy (MEC): 73% Gimore JW et al. J Oncol Pract ;10(1):68 74 Aapro M et al. Ann Oncol. 2012;23(8): Key Updates in MASCC/ESMO Guidelines Anthracycline + cyclophosphamide (AC) = high risk Inclusion of NEPA and rolapitant as NK 1 options High emetic risk non AC regimen and AC Acute CINV : 3 drug regimen (5HT 3 RA + NK 1 RA + ) Delayed CINV (Non AC) : Above + on days 2 4 Delayed CINV (AC ): No if long acting NK 1 RA used Olanzapine may be considered with a 5HT 3 RA + Carboplatin based regimen: 5HT 3 RA + NK 1 RA + No need for delayed CINV prophylaxis with Tools/mascc_antiemetics 7

8 Key Updates in NCCN Guidelines Updated yearly and periodically Anthracycline + cyclophosphamide (AC) = high risk Inclusion of NEPA and rolapitant as NK 1 options Olanzapine containing regimen added as option for high and moderate emetic risk Acute (day 1): Olanzapine + palonosetron + 20mg Delayed (day 2 4): Olanzapine 10mg daily Key Updates in ASCO Guidelines Update to 2011 guidelines Inclusion of netupitant/palonosetron as option for patients receiving high emetic risk regimens Anthracycline + cyclophosphamide (AC) = HEC Palonosetron is preferred 5HT 3 RA in moderate emetic risk regimens Guideline Recommendations: High Risk Acute CINV: Day 1 3 drug combination NK1 + 5HT3 + Dexamethasone Delayed CINV: Day 2 4 Dexamethasone 8mg PO/IV daily ESMO/MASSC NCCN ASCO *Delayed not necessary for AC *Can use Olanzapine 10mg instead of NK1 * Olanzapine 10mg daily on days 2 4 (no ) 5HT3 antagonist Aprepitant 125mg day 1, 80mg on Palonosetron 0.25mg days 2 and 3 Ondansetron 16 24mg PO, 8 16mg IV Fosaprepitant 150mg IV days 1 Dolasetron 100mg PO once Rolapitant 180mg days 1 Granisetron 2mg PO, 0.01mg/kg IV NEPA (combination of netupitant 300mg and palonosetron 0.5mg days 1 Guideline Recommendations: Moderate Risk ESMO/MASSC NCCN ASCO Acute CINV: Day 1 2 drug combination 5HT3 + Dexamethasone (Aloxi preferred 5HT 3RA) NK1 Receptor Antagonist Delayed CINV: Day 2 3 No * Carboplatin regimens No *Consider for oxaliplatin, anthracycline or cyclophosphamide Consider *Can use Olanzapine instead of NK1 ( or 5HT3) If NKI given, none * Olanzapine 10mg daily on days 2 3 No *May consider () Guideline Recommendations: Low & Minimal Risk Low Risk Minimal Risk MASSC/ESMO NCCN ASCO Single agent: 5HT3 or dexamethasone or dopamine antagonist No routine prophylaxis Single agent: 5HT3 or dexamethasone or dopamine antagonist No routine prophylaxis Single agent: Dexamethasone 8mg PO No routine prophylaxis Poll Question 1. BJ is a 45 y/o newly diagnosed female with breast cancer who presents to your clinic for her 1 st cycle of AC. Which of the following is appropriate for CINV prophylaxis on day 1 of chemotherapy? A. Netupitant/ Palonosetron mg + Dexamethasone 12mg B. Olanzapine 10mg + Palonosetron IV 0.25mg + Dexamethasone 20mg C. Rolapitant 180mg PO + palonosetron IV 0.25mg + Dexamethasone 12 mg D. Olanzapine 10mg + Aloxi IV 0.25mg + Fosaprepitant 150mg IV + Dexamethasone 12mg E. All of the above 8

9 Conclusion CINV is one of the most feared complications of chemotherapy having a serious impact on patients CINV can be prevented and pharmacists have a huge role to ensure patients receive appropriate antiemetic regimens Institutions should incorporate evidence and practice based guidelines into daily practice to optimize patient care Updates in the Management of Chemotherapy induced Nausea and Vomiting (CINV) Diwura Owolabi, Pharm.D, BCOP Clinical Pharmacy Specialist, Blood and Marrow Transplantation Methodist University Hospital, Memphis 9