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ISBP IIIB Chemotherapy Induced Nausea and Vomiting (CINV) Lecture 24 M.L. Chavez, Pharm.D., FAACP Learning Objectives • Recognize the neurotransmitters associated with chemotherapy induced nausea and vomiting • Identify the emetogenic risk potential of various chemotherapy regimens •...

ISBP IIIB Chemotherapy Induced Nausea and Vomiting (CINV) Lecture 24 M.L. Chavez, Pharm.D., FAACP Learning Objectives • Recognize the neurotransmitters associated with chemotherapy induced nausea and vomiting • Identify the emetogenic risk potential of various chemotherapy regimens • Identify appropriate treatment for anticipatory, acute, delayed, and breakthrough chemotherapy induced nausea and vomiting • Recognize the stability of compounded antiemetic medications Nausea and Vomiting • Most commonly feared side effect by cancer patients • Nausea and vomiting can result in: – Significant weight loss – Malnutrition – Dehydration – Electrolyte and acid -base imbalances – GI mucosal tears – Aspiration pneumonia Psychological Effects of Nausea and Vomiting • Anxiety • Fatigue • Anticipatory nausea and vomiting • Refusal of chemotherapy Types of Nausea/Vomiting 1. Acute - Occurs during first 24 hours after chemotherapy - Peaks at 4 -6 hours - Responsive to drug therapy 2. Delayed - Occurs >24 hours; up to 5 days after chemotherapy - Common causative agents: cisplatin , cyclophosphamide, carboplatin, doxorubicin, ifosfamide NCCN Clinical practice guidelines in oncology: Antiemesis;V1.2023 Feyer, P et al., Ann Oncol . 2011; 22:30 -8 Kris MG, et al. J Clin Oncol 2006;24:2932 -2947. Risk of CINV Chemotherapy Delayed 24 -120 hours Acute 0-24 hours Types of Nausea/Vomiting 3. Anticipatory - Psychosomatic - Emesis episodes due to sight, smell, sound, memory of previous uncontrolled N/V - Occurs <24 hours before chemotherapy - Risk factors: Treatment > 6 months with highly emetogenic agents, anxiety, depression, poor emetic control, age <50 4. Breakthrough - Occurs despite appropriate prophylaxis - Requires rescue antiemetics - Should be from a different class (receptor target) than scheduled antiemetics Risk of CINV NCCN Clinical practice guidelines in oncology: Antiemesis;V1.2021 Feyer, P et al., Ann Oncol . 2011; 22:30 -8 Chemotherapy Delayed 24 -120 hours Acute 0-24 hours Anticipatory Anticipatory N/V • Conditioned response • Caused by poor control of nausea and vomiting with previous cycles and/or extreme anxiety • Difficult to treat Risk Factors for CINV • Age <50 • Female • Predisposing factors – Hx of anxiety/depression – Hx of motion sickness – Hx of morning sickness – Hx of poor controlled CINV • Alcohol use (≥ 5 drinks/week) = LOWER risk ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting. Am J Health -Syst Pharm 1999;56:729 -64. Chemotherapy Related Factors • Intrinsic emetogenicity of chemotherapy • Dose • Route of administration • Rate of infusion • Repeated cycles of chemotherapy Pathophysiology of Nausea and Vomiting • Complex physiological process that is not fully understood • There are several neurotransmitters that stimulate neuronal discharge in the CTZ and the visceral efferent fibers Neurotransmitter Role in N & V • Histamine/muscarinic – role in vestibular etiology • Dopamine (D 2) – an additive factor – No longer considered a major component of CINV • Serotonin (5HT 3) – most important in acute CINV , but minimal serotonin release seen in delayed CINV phase • Neurokinin 1 antagonists ( NK 1) – appears to modulate acute and be most significant in delayed CINV • GABA – anxiety, increased ICP effects cerebral cortex to release GABA • Vomiting center (medulla) – H1, AchM, 5HT3 Pathophysiology: Peripheral Pathways • Chemotherapy administered • Free radicals are generated • 5 -hydroxytryptamine (5HT, serotonin) is released from enterochromaffin cells • 5HT interacts with 5HT3 receptors in the bowel wall • Signal projects to vomiting center in brain stem (dorsal vagal complex) Hesketh PJ. NEngl JMed 2008;358:2482 -94. Chemotherapy Damage to cells (e.g. intestinal cells) Release of Serotonin 5-HT3 receptor Transmission of vomiting signal Nausea/Vomiting Gastrointestinal Tract Grading of Nausea and Vomiting Nausea: inclination to vomit or feeling in throat/epigastric region alerting patient that vomiting is imminent Vomiting :forcible ejection of stomach contents through the mouth Grade 1 Grade 2 Grade 3 Grade 4 Loss of appetite without alteration of eating habits Oral intake decreased without significant weight loss, dehydration, or malnutrition Inadequate caloric or fluid intake; tube feeding, TPN, or hospitalization indicated ----- Grade 1 Grade 2 Grade 3 Grade 4 1-2 episodes in 24 hours 3-5 episodes in 24 hours >6 episodes in 24 hours; tube feeding, TPN, or hospitalization indicated Life -threatening consequences; urgent intervention indicated Common Terminology Criteria for Adverse Events. Version 4.0. ctep.cancer.gov. Treatment Strategy • Any vomiting is too much • Prevention better than treatment • Use an antiemetic regimen appropriate to the chemotherapeutic regimen • Use drugs of different mechanism of action for best effect Case 1: Risk Factors • TG is a 62 -year -old female with newly diagnosed stage II HER2 -negative breast cancer starting her first cycl e of chemotherapy using the AC -T regimen (doxorubicin/cyclophosphamide followed by weekly paclitaxel). •She is nervous about starting chemotherapy and is dreading the potential for nausea after reading about other patients’ experiences on the internet. •Social History - Married. Has two adult children. She did not report any morning sickness during her pregnancies - Non -smoker, but drinks about 1 -2 glasses of wine per month - Reports some motion sickness on long car rides - Labs are within normal limits and reports no drug allergies . Management of CINV • Principles of antiemetic use for CINV – Primary goal is to prevent nausea/vomiting throughout the period of emetic risk – Step 1: Determine emetogenic potential of anticancer agents – Selection of antiemetic regimen based on: • Chemotherapy drug with the highest emetic risk • Prior emetic experience • Patient specific factors Emetogenic Potential of Chemotherapy • Ratin g is based on vomiting without an antiemetic Risk Category Incidence of Vomiting High >90% Moderate 30 -90% Low 10 -30% Minimal <10% NCCN Clinical practice guidelines in oncology: Antiemesis;V1.2023 Case (cont.) • TG is a 62 - year - old female with newly diagnosed stage II HER2 - negative breast cancer. She is starting her first cycle of chemotherapy with AC - T regimen: – Doxorubicin 60 mg/m 2 every 2 weeks – Cyclophosphamide 600 mg/m 2 every 2 weeks – Followed by weekly paclitaxel 175 mg/m 2 • What antiemetic regimen should TG receive? Antiemetic s 5-HT 3 Antagonists Dose Half Life Ondansetron (Zofran®) IV: 8 mg PO: 8 mg 1 -2x/day Max 24mg a day 3-6 hours Palonosetron (Aloxi®) IV: 0.25 -0.5 mg 40 hours Granisetron (Kytril®) PO: 2 mg/day IV: 10 mcg/kg/day Patch: 34.3mg (apply 24 -48 hrs before D1 chemo) SQ (extended release): 10 mg (before D1 chemo) PO: 6 hours IV: 5 -9 hours Patch: N/A SQ Injection: 24 hours Dolasetron (Anzemet®) PO: 100 mg 6-8 hours MOA: peripheral AND central serotonin antagonism ADRs: headache, constipation, QTc prolongation, minimal drowsiness NCCN Clinical practice guidelines inoncology: Antiemesis; V1.202 3 Antiemeti cs NK -1 antagonists Dose Half -Life Compounding Aprepitant (Cinvanti®, Emend®) PO: 125 mg on day 1, then 80 mg on days 2 -3 IV: 130 mg x1 9-13 hours Stability: Solution for infusion in NS for 6 hours at room temp, and 72 hours refrigerated. Fosaprepitant (Emend®) IV:150 mg x1 9-13 hours Stability: Solution for infusion are stable for 24 hours at room temp. MOA: Inhibits binding of substance P at NK -1 receptor in CNS & GI tract ADRs : Fatigue, hiccups, heartburn, dizziness, mild/transient increased LFTs Drug interactions: major substrate of CYP3A4 and moderate inhibitor of CYP3A4 MOA: inhibition of prostaglandin synthesis in cortex, decreased serotonin in the CNS, modulation of emetic center in CNS ADRs: GI upset, insomnia, mood changes, increased appetite, hyperglycemia Corticosteroids Dose Half -life Dexamethasone (Decadron®) 8-12 mg PO/IV 36 -54 hours NCCN Clinical practice guidelines in oncology: Antiemesis;V1.2023 Antiemetics NCCN Clinical practice guidelines inoncology: Antiemesis; V1.202 3 Benzodiazepine Dose Half -life ADR Lorazepam (Ativan®) Alprazolam (Xanax®) 0.5 -2 mg IV/PO/SL q4 -6h 0.5 -2 mg PO TID ~12 hours 6-27 hours Sedation, respiratory depression Cannabinoid Dose Half -life ADR Dronabinol (Marinol®) 5-10 mg q3 -6h PO Alpha 4 -5 hours Terminal 25 - 36 hours Sedation, hallucinations, tachycardia, ↑ appetite MOA: activates cannabinoid receptors throughout the brain and peripheral nervous system MOA: agonize GABA receptors in CNS More effective as a sedative/anxiolytic/amnesic than anti -emetic MINIMAL No prophylactic antiemetics LOW Dexamethasone or Metoclopramide or Prochlorperazine Or 5-HT3 antagonist MODERATE Dexamethasone + 5-HT3 antagonist +/ - NK -1 antagonist olanzapine HIGH Dexamethasone +5HT3 antagonist + NK -1 antagonist +/ -olanzapine Dexamethasone NK -1 antagonist Olanzapine Palonosetron ANTICIPATORY Lorazepam Delayed N/V Therapy Based on Emetogenic Risk Day 1 +/ - Days 2-4 American Society of Clinical Oncology (ASCO) and Multinational Association for Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) Guideline s • For high or moderate emetic risk – 5HT3 + dexamethadone + olanzapine – Olanazpine is used off -label for prevention and refractory to standard antiemetics in combination with 5HT3 and dexamethadon e – Olanazpine is associated with sedation • Recommends low dose (5 mg not 10 mg) CINV Risk Summary • Intrinsic chemotherapy emetogenicity most important risk • Always use highest risk categor y • Most important risk factor for delayed N/V is acute control • Control in 1 st cycle influences other cycles • Patient risk factors affects other therapy related factors Case (cont.) • What anti - emetic regimen should TG receive? – She will receive highly emetogenic chemotherapy regimen (based on whole regimen – Dexamethasone 12mg IV – Ondansetron 16mg IV or 24mg oral – Fosapepritant 150mg IV  30 minutes prior to chemotherap y Case (cont.) • After TG’s first cycle of chemotherapy she is extremely nauseated and is not able to eat for 3 days • She is not taking any antiemetic meds • She is very nervous about her next dose of chemotherapy and just seeing her oncologist makes her nauseated What types of CINV is TG experiencing Breakthrough Anticipatory Dexamethasone Prochlorperazine PRN Palonosetron PRN Others Lorazepam PO before chemotherapy Case (cont. ) Breakthrough CINV • Dexamethasone 4-8mg PO on days 2-3 • Prochlorperazine PRN • Palonosetron PRN • Add olanzapine Anticipatory CINV Lorazepam PO before chemotherapy • Treatment of TG’s breakthrough and anticipatory CINV Case 2 • MO is a 38 -year -old male with small cell lung cancer that will receive cisplatin IV 75 mg/m 2 on day 1 and etoposide IV 100 mg/m 2 days 1 -3 . Step 1:What is the emetogenetic risk is this regimen? • Cisplatin: high • Etoposide: minimal • Whole regimen is high risk Step 2: What classes of medications should be considered for his antiemetic regimen? • 5-HT3 + steroid + NK -1 Step 3: Which antiemetic regimen should be given? • Ondansetron 8mg IV/PO + Dexamethasone 12 mg PO + fosaprepitant 125 mg IV on Day 1, followed by dexamethasone 8 mg/d x 3 days and prochloperazine PRN Ahlstrom A. Alaska Pharmacy Association Annual Meeting Ahlstrom -Slides -2022 -Chemo -Induced -Nausea -and -Vomiting.pdf (alaskapharmacy.org) Case 3 • AB is a 44 -year -old male with EGFR receptor positive non - small cell lung cancer who was started on erlotinib PO 150 mg once daily. Step 1:What is the emetogenic risk is this regimen? • Erlotinib: low -minimal Step 2: What classes of medications should be considered for his antiemetic regimen? • Dopamine antagonist or 5HT -3 or nothing Step 3: Which antiemetic regimen should be given? • Prochlorperazine 10 mg PO/IV, then PRN or • Metoclopramide 10 mg PO, then PRN or • Ondansetron 8 mg PO then PRN Cannabinoids • Marijuana, tetrahydrocannabinol (THC) and synthetic THC (Dronabinol) Cannabinoids - Mechanism of Effect • Unknown action: – May inhibit cortical input into VC – May inhibit prostaglandin synthesis and interaction with endogenous opiate receptors in the VC Dronabinol • Antiemetic activity is equal to phenothiazines • Antiemetic effect correlates to “high” – Well accepted among young adults – Poorly accepted by elderly Dronabinol - Dosage • Dronabinol (Marinol) – Dose: 5 -15 mg/m 2 po prior to chemotherapy, then q 3 -6 hrs – Should be stored in the original container in a cool place (46 o F – 59 o F or refrigerated Dronabinol • Adverse Effects – Numerous CNS effects including: • Memory loss • Motor incoordination • Mood changes • Altered sensorium • Euphoria • Hallucination Medical Cannabis • Results of small clinical trials using cannabis for CINV have found benefit – Recent worldwide expensive DBPC study ($21 million) with 81 patients receiving standard antiemetics and oral cannabis found less N/V but needs to be repeated with large sample size • Grimison P, et al. https://www.annalsofoncology.org/article/S0923 - 7534(20)39996 -8/fulltext/ – There are many barriers to conducting cannabis researc h Summary of Management of CINV Prevention of Acute CINV • Highly emetogenic regimens – 5HT 3 antagonist ± NK 1 + dexamethason e ± BZ • Moderately emetogenic regimens – 5HT 3 antagonist + dexamethason e ± BZ – D 2 antagonist + dexamethason e ± BZ • Low emetogenicity regimens – Nothing vs. D 2 antagonists Breakthrough CI NV • Add an agent from a different drug class • Schedule antiemetic therapy rather than PRN dosing • Use multiple agents with different mechanisms of action • Use PR or IV route when PO is not an option • Alter preventative therapy for next cycle of chemotherapy NCCN Clinical practice guidelines in oncology: Antiemesis; V1.2 023 1 . Breakthrough Agents • Prochlorperazine • Promethazine • Olanzapine • Lorazepam • Metoclopramide • Haloperidol • Dexamethasone • Dolasetron • Ondansetron • Graniosetron • Dronabinol Anticipatory CINV • Control CINV from first cycle • Calming music/distraction therapy • Muted colors in room • Benzodiazepines – lorazepam (Ativan) or alprazolam (Xanax) – Anterograde amnesia effects helpful Pharmacists Management of CINV • Studies have shown pharmacists can improve patient’s quality of life while on cancer treatment by preventing nausea and vomiting Colombo LRP, et al. J Clin Pharm Ther 2017: 42(4)414 -424 https://www.pngwing.com/en/search?q=woman+Pharmacist