Disclosure Oncologic Emergencies and Acute Supportive Care of the Critically Ill Oncology Patient By: Kimberly Regis, Pharm.D. Broward Health Medical Center Pharmacy Resident 2014-2015 I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation 2 Objectives Upon completion of this activity, the pharmacist should be able to: Identify common complications of chemotherapy and assess the administration of relevant treatment Discuss applicable non-pharmacologic and pharmacologic treatment for cancer related pain Evaluate and recommend appropriate pharmacotherapy for the management of oncology related emergencies Objectives Upon completion of this activity, the technician should be able to: Examine causes or areas where medication errors frequently occur and the technician s role in minimizing medication errors Analyze potential barriers to rapid preparation and delivery of cancer related medications Outline suitable handling and storage techniques for hazardous medications 3 4 Oncologic Emergency 1 Classification of Emergencies 1 Oncologic emergency Complications resulting from a cancer itself or from the treatment of the cancer that requires immediate attention Can be classified by their system of origin: Metabolic Neurologic Cardiovascular Hematologic Infectious Classification Oncologic Emergency Metabolic Hypercalcemia Tumor Lysis Syndrome Neurologic Spinal Cord Compression Cardiovascular Superior Vena Cava Syndrome Hematologic Disseminated Intravascular Coagulation (DIC) Infectious Neutropenic Fever Septic Shock 5 6 1
Hypercalcemia 1 Management of Hypercalcemia 1 Results from increased bone resorption with calcium release into the extracellular fluid; renal clearance of calcium is also decreased Most common tumors associated with hypercalcemia are: Lung Breast Multiple myeloma Head and neck Renal cell Non-Hodgkin s lymphoma 7 Mild Corrected calcium less than 12 mg/dl May not require aggressive treatment Asymptomatic patients: hydration with normal saline followed by observation is an option Moderate Corrected calcium 12 14 mg/dl Requires basic treatment of clinical symptoms 8 Management of Hypercalcemia 1 Tumor Lysis Syndrome (TLS) 1 Severe Corrected calcium greater than 14 mg/dl Patient is usually symptomatic Requires aggressive inpatient treatment Treatment options Hydration with normal saline Loop diuretics Bisphosphonates Calcitonin Steroids Phosphate Dialysis Cyclooxygenase inhibitors 9 1. Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci 2007; 4(2):83-93. doi:10.7150/ijms.4.83. Available from http://www.medsci.org/v04p0083.htm 10 TLS Management 1,2 Spinal Cord Compression 1,2 Primary management is prevention with intravenous hydration (NaCl), sodium bicarbonate, and allopurinol Rasburicase (Elitek ) recombinant urate oxidase converts uric acid into allantoin Considered for patients at high risk of developing tumor lysis syndrome or inability to take allopurinol Direct extension from a metastasis in the vertebral body Signs and symptoms include Back pain Weakness Paresthesias Unsteady gait Loss of bowel and bladder function Treatment: dexamethasone and radiation therapy or surgery 2. Cervantes A., Chirivella I. Oncologic emergencies. Annals of Oncology 15 (Supplement 4): iv299 iv306, 2004 11 2. Kaplan, Marcelle, (2006). Understanding and Managing Oncologic Emergencies: A resource for nurses. Oncology Nursing Society, Philadelphia 12 2
Superior Vena Cava Syndrome 1 Disseminated Intravascular Coagulation (DIC) 1 Blood flow through the superior vena cava is compressed Causes decreased venous return to the heart, decrease in cardiac output, and increase in venous congestion and edema Treatment includes Chemotherapy/radiation Stent placement Diuretics Corticosteroids Thrombolytic agents 13 Inappropriate activation of the coagulation cascade, resulting in thrombosis and hemorrhage Solid tumors are associated with chronic DIC Two pathways Extrinsinc Intrinsic Treatment includes: Treat underlying problem Plasmapheresis Hemodynamic support IV fluids Oxygen Low dose Heparin May reverse the clot formation 14 Neutropenic Fever 1 MASCC Risk Index 1 Neutropenia: ANC of 500/mm 3 or less or a count of < 1000/mm 3 with a predicted decrease to < 500/mm 3 during the next 48 hours Fever: single oral temperature of 101 F or more or a temperature of 100.4 F or more for at least 1 hour Fever is often the only indicator 15 1. National Comprehensive Cancer Network (NCCN). Supportive Care: Febrile Neutropenia (Version 1.2014). http://www.nccn.org. 16 Neutropenic Fever Treatment 1 Neutropenic Fever Treatment 1 First approach IV monotherapy First approach PO therapy Imipenem-Cilastatin (Primaxin ) Ciprofloxacin (Cipro ) + Amoxicillin/Clavulanate (Augmentin ) Meropenem (Merrem ) Allergy to penicillin - Ciprofloxacin (Cipro ) + Clindamycin (Cleocin ) Ceftazidime (Fortaz ) Cefepime (Maxipime ) Allergy to penicillin - Aztreonam (Azactam ) + Vancomycin (Vancocin ) Second approach IV dual therapy Aminoglycoside plus anti- pseudomonal penicillin OR an extended spectrum antipseudomonal cephalosporin Ciprofloxacin plus anti- pseudomonal penicillin Third approach for therapy Combination of monotherapy or dual therapy plus IV Vancomycin for specific indications - Not used as initial therapy because of vancomycin resistant organisms 1. National Comprehensive Cancer Network (NCCN). Supportive Care: Febrile Neutropenia (Version 1.2014). http://www.nccn.org. 17 1. National Comprehensive Cancer Network (NCCN). Supportive Care: Febrile Neutropenia (Version 1.2014). http://www.nccn.org. 18 3
Criteria for Therapy Discontinuation 1 Negative cultures for 48 hours Afebrile for 24 hours Evidence of marrow recovery (increase in ANC to >1000 cells/µl) It is acceptable to send an afebrile patient home for marrow recovery if the patient was a low risk patient 1. National Comprehensive Cancer Network (NCCN). Supportive Care: Febrile Neutropenia (Version 1.2014). http://www.nccn.org 19 Septic Shock 1 Sepsis: bodily response to infection Two of the following Temperature > 100.4 F or < 96.8 F HR > 90 bpm RR > 20 bpm WBC >12,000 or < 4,000, or > 10% immature bands Severe sepsis: hypo-perfusion with hypotension or organ dysfunction Septic shock: persistent hypotension with organ dysfunction 20 Septic Shock Treatment 1 Acute Supportive Care 1 Blood, throat, wound, and urine cultures Labs (CBC, Chemistry, Coagulation), ABGs, CXR, EKG Fluids to improve perfusion/increase blood pressure Antibiotics Oxygen Electrolyte replacement 21 Interventions that help the patient achieve comfort but do not affect the course of the disease Acute Supportive Care Chemotherapy induced nausea and vomiting (CINV) Extravasation Thrombocytopenia Anemia Cancer-related pain 22 Chemotherapy Induced Nausea and Vomiting(CINV) 1,2 Basic Definitions: Nausea: discomfort that may or may not precede vomiting; decreased gastric tone and peristalsis Retching: dry heaves Vomiting: ejection of gastric contents through the mouth Acute onset Delayed onset Chemotherapy Induced Nausea and Vomiting(CINV) 1,2 Basic Definitions Anticipatory vomiting/nausea: triggered by sights, smells, or sounds Breakthrough emesis: vomiting occurs despite prophylactic treatment; requires rescue medications Refractory: emesis occurs during treatment when prophylactic treatment has failed in previous cycles 23 24 4
Management of CINV 1,2 High Emetogenic Potential IV Agents 1,2 Prophylaxis is key! Administer prophylactic anti-emetics before moderately or highly emetogenic agents Make sure anti-emetic regimen is appropriate based on the emetogenicity of the agent For select chemotherapy agents, schedule anti-emetics for delayed nausea and vomiting Greater than 90% frequency of emesis AC (combination defined as either doxorubicin or epirubicin with cyclophosphamide) Carmustine > 250 mg/m 2 Cisplatin 50 mg/m 2 Cyclophosphamide >1500 mg/m 2 Dacarbazine Doxorubicin > 60 mg/m 2 Epirubicin > 90 mg/m 2 Ifosfamide 10 g/m 2 Mechlorethamine 25 26 Moderate Emetogenic Potential IV Agents 1,2 Low Emetogenic Potential IV Agents 1,2 Aldesleukin > 12 15 million IU/m 2 Amifostine > 300 mg/m 2 30-90% frequency of emesis Dactinomycin Daunorubicin Arsenic trioxide Doxorubicin < 60 mg/m 2 Azacitidine Idarubicin Bendamustine Ifosfamide < 10 g/m 2 Busulfan Interferon alfa 10 million IU/m 2 Carboplatin Carmustine 250 mg/m 2 Irinotecan Melphalan Cisplatin < 50 mg/m 2 Methotrexate 250 mg/m 2 Clofarabine Cyclophosphamide 1500 mg/m 2 Oxaliplatin Temozolomide 10-30% frequency of emesis Aldesleukin 12 million IU/m 2 Ixabepilone Amifostine 300 mg Methotrexate > 50 mg/m 2, < 250 mg/m 2 Cabazitaxel Mitomycin Cytarabine (low dose) 100 200 mg/m 2 Mitoxantrone Docetaxel Paclitaxel Doxorubicin (liposomal) Paclitaxel-albumin Eribulin Pemetrexed Etoposide Penostatin Fluorouracil Romidepsin Floxuridine Thiotepa Gemcitabine Topotecan Cytarabine > 200 mg/m 2 Interferon alfa > 5 < 10 million IU/m 2 27 28 Alemtuzumab Minimal Emetogenic Potential IV Agents 1,2 < 10% frequency of emesis Ipilimumab Asparaginase Methotrexate 50 mg/m 2 Bevacizumab Bleomycin Bortezomib Cetuximab Cladribine (2-chlorodeoxyadenosine) Cytarabine < 100mg/m 2 Decitabine Denileukin diftitox Dexrazoxane Fludarabine Interferon alfa 5 million IU/m 2 Nelarabine Ofatumumab Panitumumab Pegasparagase Rituximab Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vinorelbine 29 Altretamine Busulfan ( 4 mg/day) Etoposide Lomustine (single day) Bexarotene Busulfan (< 4 mg/day) Cyclophosphamide (< 100 mg/m 2 /day) Hydroxyurea Fludarabine Melphalan Mercaptopurine Vorinostat Topotecan Prophylaxis Recommended for Oral Agents Cyclophosphamide ( 100 mg/m 2 /day) Estramustine Procarbazine As Needed for Oral Agents Temozolomide (> 75 mg/m 2 /day) Capecitabine Chlorambucil Dasatinib, Erlotinib, Imatinib, Lapatinib, Nilotinib, Sorafenib, Sunitinib, Pazopanib, Vandetanib, Gefitinib Everolimus Tretinoin Methotrexate Lenalidomide, Thalidomide, Temozolomide ( 75 mg/m 2 /day) Thioguanine 30 5
CINV Treatment Options CINV Treatment 1,2 Drug Day 1 Day 2 Day 3 Day 4 Aprepitant (Fosaprepitant IV) AND 125 mg PO or 150 mg IV 80 mg PO 80 mg PO N/A Dexamethasone AND Ondansentron OR Granisetron OR Dolasetron OR Palonosetron 12 mg PO/IV 12 mg PO/IV 16-24 mg PO or 8-16 mg IV 2 mg PO or 0.01 mg/kg IV (max 1 mg) or Sancuso Patch 8 mg PO 8 mg PO 8 mg PO 8 mg PO BID N/A N/A N/A N/A N/A N/A 100 mg PO N/A N/A N/A 0.25 mg IV 8 mg PO 8 mg PO BID 31 32 Extravasation 1 Extravasation Definition: the leakage or escape of a drug/solution from a vein or inadvertent injection into surrounding tissues Three types of chemotherapy agents Non-vesicant Irritant Vesicant Non-DNA binding DNA binding 1. Ackerman M., Allen C., Armbruster W., et al. Extravasation Guideliness. Children s Oncology Group, 2007. 33 34 Management of Extravasation 1 Stop the infusion and disconnect the IV tubing Apply a topical compress (warm or cold depending on offending agent) Next, antidote should be infused and any pharmacologic treatments should be given as well Photograph site of initial injury and on all other visits Follow-up visits are needed for assessment Medication Cisplatin (Platinol ) Extravasation Potential Vesicant at concentration > 0.4 mg/ml Local Care Cold Compress Teniposide (Vumon ) Irritant/Vesicant Cold Compress, Warm Compress Anthracyclines (Daunorubicin, Doxorubicin, Idarubicin) Antidote Sodium Thiosulfate vs. Dimethyl Sulfoxide (DMSO) Hyaluronidase Vesicants Cold Compress Dexrazoxane vs. DMSO Etoposide (Vepesid ) Vesicant/Irritant Warm Compress Hyaluronidase Mitomycin (Mutamycin ) Mitoxantrone (Novantrone ) Vesicant None or Cold Compress Dimethyl Sulfoxide vs. Sodium Thiosulfate Irritant/Vesicant Cold Compress Dezrazoxane vs. DMSO Oxaliplatin (Eloxatin ) Irritant/Vesicant None None Paclitaxel (Taxol ) Irritant/Vesicant Cold Compress Hyaluronidase Vinca Alkaloids (Vinblastine, Vincristine, Vinorelbine) Vesicants Warm Compress Hyaluronidase 1. Ackerman M., Allen C., Armbruster W., et al. Extravasation Guideliness. Children s Oncology Group, 2007. 35 1. Ackerman M., Allen C., Armbruster W., et al. Extravasation Guideliness. Children s Oncology Group, 2007. 36 6
Medication Bleomycin (Blenoxane ) Carboplatin (Parplatin ) Extravasation Potential Local Care Antidote Irritant Cold Compress None Irritant at > 10mg/mL Cold Compress DMSO Carmustine (BiCNU ) Vesicant/Irritant Cold Compress None Cyclophosphamide (Cytoxan ) Dacarbazine (DTIC- DOME ) Dactinomycin (Cosmegen ) Irritant Cold Compress None Irritant/Vesicant Cold Compress DMSO Vesicant Cold Compress DMSO Docetaxel (Taxotere ) Vesicant/Irritant Cold Compress None Fluorouracil (Adrucil ) Topotecan (Hycamtin ) Irritant None Possibly DMSO Irritant Cold Compress None Medication Gemcitabine (Gemzar ) Extravasation Potential Local Care Antidote Irritant None None Ifosfamide (Ifex ) Irritant Cold Compress Possibly DMSO Irinotecan (Camptosar ) Mechlorethamine (Mustargen ) Irritant Ice None Vesicant None Sodium thiosulfate Melphalan (Alkeran ) Irritant/Vesicant Cold Compress None 1. Ackerman M., Allen C., Armbruster W., et al. Extravasation Guideliness. Children s Oncology Group, 2007. 37 1. Ackerman M., Allen C., Armbruster W., et al. Extravasation Guideliness. Children s Oncology Group, 2007. 38 Thrombocytopenia 1 Anemia 1 Platelet count < 100,000/mm 3 Oprelvekin (interleukin-11) Approved for the prevention of severe thrombocytopenia in patients undergoing chemotherapy for non-myeloid malignancies Daily subcutaneous injection, beginning 6 24 hours after completion of chemotherapy Continue until a post-nadir platelet count of 50,000 cells/mm 3 or greater Dosing beyond 21 days is not recommended Must be discontinued at least 2 days before the next cycle of chemotherapy 39 Decreased RBC production due to chemotherapy Treatment: Erythropoiesis stimulating agents (ESA s) Epoetin alfa (Epogen, Procrit ) Darbepoetin alfa (Aranesp ) Only if hemoglobin < 10 g/dl and duration of chemotherapy 2 months Discontinue after completion of chemotherapy 40 Cancer Related Pain Principles 1 When available, the oral route is preferred The dose and analgesic drug should match the severity of pain suffered by patient Pain medications should always be administered on a scheduled basis, not as needed If more than two as-needed doses are required for breakthrough pain in a 24-hour period, consider modifying the regimen Provide medications to prevent adverse events (e.g., constipation) Pain Rating Scales 1 Use pain scales to evaluate pain intensity at baseline and throughout regimen Pain is subjective; best evaluated by the patient 41 42 7
WHO Analgesic Ladder 1 Medication Errors 1 Preventable event that may cause patient harm or inappropriate medication use while the medication is in control of the healthcare professional, patient, or consumer Potential error: mistake in prescribing, dispensing, or planned administration that is corrected prior to actual medication administration 1. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Can Fam Physician.2010 Jun;56(6): 514-517. Accessed: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2902929/ 43 1. American Society of Hospital Pharmacists. ASHP guidelines on preventing medication errors in hospitals. Am J Hosp Pharm. 1993; 50:305 14. 44 Types of Medication Errors 1 Common Causes of Medication Errors 1 Type Definition Prescribing Error Incorrect drug selection; illegible script Omission Error Failure to do something correctly Wrong Time Error Giving a drug outside predefined time Unauthorized Drug Error Giving a drug not authorized by MD Improper Dose Error Dose is greater or less than that ordered Wrong Dosage Form Error Administration of a different dosage form Wrong Drug Preparation Error Incorrectly formulated or manipulated Wrong Administration Technique Error Inappropriate procedure or technique Deteriorated Drug Error Giving an expired drug Monitoring Error Failure to assess prescribed regimens Compliance Error Non-adherence to regimen Other Errors Those who don t fall in above categories 1. American Society of Hospital Pharmacists. ASHP guidelines on preventing medication errors in hospitals. Am J Hosp Pharm. 1993; 50:305 14 45 Ambiguous strength designation on labels or in packaging Drug product nomenclature (look-alike or sound-alike names, use of lettered or numbered prefixes and suffixes in drug names) Equipment failure or malfunction Illegible handwriting Improper transcription 1. American Society of Hospital Pharmacists. ASHP guidelines on preventing medication errors in hospitals. Am J Hosp Pharm. 1993; 50:305 14 Inaccurate dosage calculation Inadequately trained personnel Inappropriate abbreviations used in prescribing Labeling errors Excessive workload Lapses in individual performance Medication unavailable 46 Prevention of Medication Errors 1 Five Rights Work area should have adequate lighting, low noise, and few distractions Drugs should be organized to reduce confusion (LASA, Tall man lettering, etc.) Remembering do not use abbreviations Adhering to pharmacy policies and procedures Prioritizing workload Recognizing strength and dosing regimen of chemotherapy Identifying weaknesses in processes Potential Barriers 1 Inappropriate dosage calculations Reading the label incorrectly Grabbing the wrong drug for preparation Taking on more than one task at a time Using inappropriate admixtures Lack of knowledge Sterile processing before drug preparation Inappropriate work area 1. Pharmacy Technician s Letter. Medication Safety: Strategies for Preventing Medication Errors. Volume 2013, Course Number 310. 47 1. Pharmacy Technician s Letter. Medication Safety: Strategies for Preventing Medication Errors. Volume 2013, Course Number 310. 48 8
Handling and Storage 1 Handling and Storage 1 Make sure pharmacy is up to date with USP 797 Wear double gloving for all activities involving hazardous drugs Personal protective equipment (PPE) must be worn at all times in the area where the preparation of chemotherapy takes place Hazardous drug spill kits, containment bags, and disposal containers must be available in all areas where hazardous drugs are handled Storage areas for hazardous drugs must have distinctive labels Hazardous drugs should be stored in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants Hazardous drugs placed in inventory must be protected from potential breakage by storage in bins that have high fronts and on shelves that have guards to prevent accidental falling 1. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172 93 49 1. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172 93. 50 Summary Summary Oncologic emergencies can be classified by their system of origin Before the administration of therapy for hypercalcemia, analyze if therapy is indicated Rasburicase (Elitek ) is only used for tumor lysis syndrome in high risk patients and those unable to take allopurinol Treatment for spinal cord compression includes dexamethasone to decrease the inflammation Superior vena cava syndrome causes a decrease in cardiac output DIC is the inappropriate activation of the coagulation cascade Fever is often the only indicator of neutropenic fever Septic shock is defined as persistent hypotension with organ dysfunction Prophylaxis is key in the management of CINV There are three types of chemotherapy agents for extravasation: non-vesicant, irritant, vesicant Do not use Oprelvekin for more than 21 days for thrombocytopenia ESA s for anemia can only be used if hemoglobin is < 10 g/dl Pain scales are utilized to evaluate pain severity One way to prevent medication errors is by remembering the five rights Knowing potential barriers to chemotherapy preparation can help prevent them from happening All hazardous drugs have a medication safety data sheet (MSDS) 51 52 During tumor lysis syndrome, there is an increase in uric acid and potassium but a decrease in phosphorous Causes of medication errors include labeling errors, look-alike sound-alike medications, inaccurate dosage calculations, and illegible handwriting FALSE Increase in uric acid, potassium, AND phosphorous TRUE 53 54 9
The following CINV regimen is standard treatment for cancer medications with high risk Aprepitant/Fosaprepitant PLUS Ondansetron PLUS Lorazepam PLUS Dexamethasone FALSE Lorazepam is not considered standard therapy for high CINV risk treatment 55 Basic storage of hazardous agents include Keeping storage areas appropriately ventilated, well lit, and at a consistent temperature TRUE 56 Performing ratio and proportion calculations mentally is the quickest and safest way to ensure that the patient gets their chemotherapy in a timely fashion Chemotherapy agents can be divided into three main categories: non-vesicants, irritants, and vesicants TRUE FALSE Chemotherapy calculations should never be performed mentally 57 58 Literature Sources Kaplan, Marcelle, (2006). Understanding and Managing Oncologic Emergencies: A resource for nurses. Oncology Nursing Society, Philadelphia Norris, LB. Oncology Supportive Care. ACCP Updates in Therapeutics, 2012. Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci 2007; 4(2):83-93. doi:10.7150/ijms.4.83. Available from http://www.medsci.org/v04p0083.htm Cervantes A., Chirivella I. Oncologic emergencies. Annals of Oncology 15 (Supplement 4): iv299 iv306, 2004 National Comprehensive Cancer Network (NCCN). Supportive Care: Febrile Neutropenia (Version 1.2014). http://www.nccn.org Literature Sources Basch E., Prestrud AA., Hesketh PJ., et al. Antiemtics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 29:4189-4198. Ackerman M., Allen C., Armbruster W., et al. Extravasation Guideliness. Children s Oncology Group, 2007. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Can Fam Physician.2010 Jun;56(6): 514-517. Accessed: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2902929 American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172 93 Pharmacy Technician s Letter. Medication Safety: Strategies for Preventing Medication Errors. Volume 2013, Course Number 310 59 60 10