Chemotherapy Induced Nausea and Vomiting Haley Gill, BSP VCH-PHC Pharmacy Resident 2009-2010

Outline Review the pathophysiology of chemotherapy induced nausea and vomiting (CINV) Review the different categories of CINV Review the pharmacologic agents indicated for CINV Review the current guidelines for CINV

Consequences of CINV medical complications quality of life electrolyte imbalances dehydration quality of life impact daily functioning compliance with chemotherapy

Pathophysiology of CINV Chemotherapy agents directly activate the CTZ which in turn releases neurotransmitters that stimulates the vomiting center in the medulla. Chemotherapy agents can irritate GI mucosa, resulting in release of neurotransmitters which activates receptors to send signals to the vomiting center in the medulla

Pathophysiology of CINV This slide depicts some of the neurotransmitters involved in vomiting: dopamine, acetylcholine, histamine, substance P, and serotonin.1 Substance P works by binding to NK 1 receptors in the midbrain which activates the vomiting center

Classification of CINV Acute within 24 hours of chemotherapy Delayed occurs > 24 hours after chemotherapy Anticipatory prior to chemotherapy Breakthrough while receiving prophylactic antiemetics Refractory Not responsive to therapy Delayed – specific chemo known to cxs (carboplatin, doxorubicin, cyclophosphamide). More common in pts who develop acute Anticipatory can be triggered by smell, taste, anxiety, etc. Conditioned response, memory of bad reaction to last chemo cycles

Neurotransmitter Involvement

Risk Factors Young age Female History of low alcohol intake Experience of emesis during pregnancy Emetogenic potential of chemotherapeutic agent History of motion sickness

Antiemetic Agents Serotonin 5-HT3 Receptor Antagonists (5-HT3 RA) Corticosteroids Dopamine-Serotonin Receptor Antagonists Dopamine Receptor Antagonists Neurokinin-1 Receptor Antagonists (NK-1 RA) Benzodiazepines Cannabinoids

Serotonin 5-HT3 RA’s Block 5-HT3 receptors in the CNS and GI tract Equivalent in efficacy and toxicities More effective for acute CINV AE’s: headache, constipation, QTc interval prolongation

Serotonin 5-HT3 RA’s Available Agents Recommended Dose Ondansetron (Zofran®) IV: 8 mg or 0.15 mg/kg PO: 8 - 24 mg dolasetron (Anzemet®) IV: 100 mg or 1.8 mg/kg PO: 100 mg granisetron (Kytril®) IV: 1 mg or 0.01 mg/kg PO: 1 - 2 mg At approved doses, the oral formulation is therapeutically equivalent to the IV dosage form. **single-daily dose schedules are similar in efficacy to multiple-daily dosing**

Corticosteroids Dexamethasone (Decadron®) Dose: 8 - 20 mg IV or PO Effective for both acute and delayed CINV MOA: unknown AE’s: Insomnia, hyperglycemia, heartburn Dexamethasone most commonly used. Methylprednisolone mentioned in some guidelines

Dopamine-Serotonin Receptor Antagonists Metoclopramide (Maxeran®) 10-30 mg IV/PO Q4-6H ac Domperidone (Motilium®) 10-20 mg PO Q4-6H ac  doses = dopamine antagonist effects  doses = serotonin antagonist effects AE’s: sedation, EPS, diarrhea Diphenhydramine (Benadryl®) may  EPS May see greater efficacy with higher doses b/c then get Serotonin blocking effects as well. EPS, Akasthesia (restlessness)

Dopamine Receptor Antagonists prochlorperazine (Stemetil®) 5 -10 mg IV/PO Q6H haloperidol (Haldol®) 0.5 – 2 mg PO/SC Q6-12H MOA: block dopamine receptors in the CTZ AE’s: EPS, disorientation, sedation

Neurokinin-1 Receptor Antagonists Aprepitant (Emend®), Fosaprepitant (IV) Dose: 125 mg PO on day 1 then 80 mg PO daily on days 2 & 3 MOA: blocks NK-1 receptor in brainstem emetic center & GI tract AE’s: fatigue, asthenia, hiccups Drug interactions:  dose of dexamethasone by 50% Can give the day 1 dose IV. Asthenia = lack of strength, malaise, fatigue Not on formulary at VGH, not a benefit for pharmacare.

Other Agents Agent Dose Use Lorazepam (Ativan ®) 0.5 - 2 mg IV/PO/SL Anticipatory N&V Cannabinoids dronabinol (Marinol®) nabilone (Cesamet®) 2.5 – 10 mg PO TID - QID Refractory & Breakthrough N&V Olanzapine (Zyprexa®) 2.5 – 10mg PO hs Acute, Delayed & Refractory N&V Gabapentin (Neurontin®) Delayed Cannabinoids role yet to be determined. Approved for refractory suggested for breakthrough. Do have some beneficial Se’s such as sedation and euphoria. Very little evidence for gabapentin

Chemotherapy Emetic Risk Groups High Risk in nearly all patients (>90%) Cyclophosphamide (high dose), cisplatin Moderate Risk in 30% to 90% of patients Daunorubicin, cytarabine (high dose), melphalan (high dose), azacitadine Low Risk in 10% to 30% of patients fludarabine, cytarabine (low dose) Minimal Fewer than 10% at risk bortezomib, vincristine, hydroxyurea Some literature suggests that all SCT conditioning regimens are high risk.

Guidelines Multinational Association of Supportive Care in Cancer (MASCC) American Society of Clinical Oncology (ASCO) National Comprehensive Cancer Network (NCCN)

Highly Emetogenic Chemotherapy Acute Delayed MASCC 5-HT3RA + dexamethasone + aprepitant Dexamethasone + aprepitant ASCO NCCN 5-HT3RA + dexamethasone + aprepitant ± lorazepam Dexamethasone + aprepitant ± lorazepam Antiemetics for delayed CINV given on days 2&3 (aprepitant) and 2-4 dexameth Conflicting results for the use of 5Ht3 RA’s for delayed. Monotx not as great as 5HT3RA + dex. Continuing a 5HT3 RA beyond 24 hrs along with dex did not confer any additional benefit compared to corticosteroids alone. Metoclop an option for delayed. Shown to be as effective as 5HT3RA when combined with dex.

Moderately Emetogenic Chemotherapy Acute Delayed MASCC 5-HT3RA + dexamethasone Dexamethasone or 5-HT3RA ASCO NCCN 5-HT3RA + dexamethasone ± lorazepam ± lorazepam Anthracycline + cyclophosphamide treated like high risk melphalan

Low Emetogenic Chemotherapy Acute Delayed MASCC dexamethasone No Routine Prophylaxis ASCO NCCN dexamethasone ± lorazepam or prochlorperazine ± lorazepam or metoclopramide ± lorazepam Anthracycline + cyclophosphamide treated like high risk

Minimal Emetogenic Chemotherapy Acute Delayed MASCC No Routine Prophylaxis ASCO NCCN Anthracycline + cyclophosphamide treated like high risk

Rescue Therapy Add an agent from another class phenothiazine, metoclopramide, or dexamethasone 5-HT3 RA unlikely to be beneficial if N & V developed with 5-HT3 RA prophylaxis Aprepitant NOT for established N & V Consider non-chemo causes Very unlikely that established N & V will respond to an agent in the same drug class after unsuccessful prophylaxis with an agent with the same mechanism of action Other causes: opiods, hypocalcemia, antibiotics, etc.

Refractory Therapy Consider adjusting pre and post chemo regimen Little data Some evidence for aprepitant & palonosetron (not in Canada)

Patient Education Very important!! Instruct patients to take their rescue drugs when nausea first begins May need to use regularly scheduled rescue drugs Additional doses of 5-HT3 RA not more effective than other rescue drugs

Cost Drug Cost/day Aprepitant ~$33.00, $99.60 (tri-pack) Ondansetron IV $1.80 PO $8.70 Dexamethasone IV $1.52 PO $1.64 Lorazepam IV $0.48 PO $0.05 Metoclopramide IV $11.60 PO $0.72 Prochlorperizine IV $4.68 PO $0.56 Ondansetron IV is 8mg dose Ondansetron PO is 8mg po bid or 16mg daily Dexa 8mg IV daily or 8mg po daily Lorazepam 1mg IV daily or 1mg po daily Maxeran 30mg IV q6h, 30mg po q6h Stemetil 10mg IV q6h, 10mg PO q6h

Questions?

References Kris MG, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. J Clin Oncol 2006;24(18):2932-47 Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008;358:2482-94 Baker PD, et al. The Pathophysiology of Chemotherapy-Induced Nausea and Vomiting. Gastroenterology Nursing 2005;28(6):469-80 Navari RM. Pharmacological Management of Chemotherapy-induced Nausea and Vomiting: Focus on Recent Developments. Drugs 2009;69(5):515-33 Jordan K, et al. Guidelines for Antiemetic Treatment of Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future Recommendations Oncologist 2007;12;1143-1150 Multinational Association of Supportive Care in Cancer Antiemetic Guidelines (last update: March 2008). Available at www.mascc.org National Comprehensive Cancer Network Antiemetic Guidelines 2007. Available at www.nccn.com

Emetic Risk Prophylaxis of acute CINV on day of chemo administration Prophylaxis of delayed CINV High 5-HT3RA + dexamethasone + aprepitant Days 2 & 3 after Chemotherapy: dexamethasone + aprepitant Moderate Anthracycline + Cyclophosphamide: Days 2 & 3 after chemotherapy: aprepitant All other regimens of moderate emetic risk: 5-HT3RA + dexamethasone Days 2-4 after chemotherapy: dexamethasone or 5-HT3RA Low Dexamethasone None Minimal