Navigating Safely Through Uncharted Waters: Overcoming the Challenges of Oral Oncolytic Therapies with a Specialized Crew Mitchell E. Hughes, PharmD, BCPS, BCOP Clinical Pharmacy Specialist-Hematology/Oncology The Abramson Cancer Center for Advanced Medicine at Penn Medicine Objectives At the completion of this activity, the participant will be able to: 1. List risks associated with dispensing oral oncolytic agent 2. Recognize potential barriers to implementation of a vigilance program for oral oncolytic agents 3. Discuss strategies to improve safety and communications involved with dispensing oral oncolytic agents 2 Disclosure “I have not received any commercial or financial support for this program” 3 Oral Chemotherapy Definition “Any drug you take by mouth to treat cancer. Oral chemo is not given to you with a needle. It’s a liquid or pill that you swallow.” “Chemo you swallow is as strong as other forms of chemo and works just as well. You take oral chemo at home” “But oral chemo drugs cost a lot” –The American Cancer Society 4 Image available from: https://localtvwiti.files.wordpress.com/2014/03/chemo-pills.jpg?quality=85&strip=all https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/oral-chemotherapy.html Misconceptions Oral chemotherapy is less toxic than intravenous (IV) chemotherapy Oral chemotherapy requires less monitoring than IV Patients will be able to start therapy the day oral chemotherapy is prescribed Oral chemotherapy does not involve any hazardous precautions 5 Image available from: http://www.ideastorenepal.com/Upload/Ideas/f434627b-a017-42cd-aded-8fba881b9bd4.jpg FDA Approvals 1953-1999 1990: Altremtamine 1995: Anastrozole, biclutamide 1953: Mercaptopurine, 1996: Nilutamide methotrexate 1997: Letrozole 1954: Busulfan 1970: Mitotane 1998: Capecitabine, 1957: Chlorambucil 1976: Lomustine thalidomide 1959: Cyclophosphamide 1977: Tamoxifen 1999: Exemestane, temozolomide, bexarotene 1964: Melphalan 1981: Estramustine 1966: Thioguanine 1986: Etoposide 1967: Hydroxyurea 1989: Flutamide 1969: Procarbazine Number of Oral Agents Approved Between 1953 and 1999: 25 over 46 years 6 https://www.fda.gov/ FDA Approvals 2000-2017 2001: Imatinib 2013: Sorafenib, ibrutinib, afatinib, trametinib, 2003: Gefitinib dabrafenib, erlotinib, pomalidomide 2004: Erlotinib, trentinoin 2014: Olaparib, ruxolitinib, idelalisib, ceritinib 2005: Sorafenib, lenalidomide 2015: Alectinib, ixazomib, osimertinib, 2006: Dasatinib, sunitinib, vorinostat trifluridine/tiperacil, eltrombopag, sonidegib, 2007: Topotecan, nilotinib, lapatinib gefitinib, panobinostat, lenvatinib, palbociclib, 2009: Everolimus, pazopanib cobimetinib 2011: Ruxolitinib, vandetanib, crizotinib, 2016: Rucaparib, levatinib, venetoclax vemurafenib, abiraterone 2017: Olaparib, enasidenib, neratinib, brigatinib, 2012: Vismodegib, axitinib, bosutinib, niraparib, ribociclib regorafenib, enzalutamide, cabozatinib, ponatinib Number of Oral Agents Approved Number of Oral Agents Approved Between 2001 and 2012: 26 over 12 Between 2013 and 2017: 31 over 5 years years 7 https://www.fda.gov/ Relevance 30-35% of antineoplastics in development are oral formulations 63-89% of patients prefer oral therapy Challenges: Drug acquisition Insurance reimbursement Oral Agents Oral Agents Oral Agents Approved: Approved: Approved: Compliance 1953-1999 2001-2012 2013-2017 Pharmacologic interactions 25 over 46 26 over 12 31 over 5 Patient education years years years Safe handling Financial impact 8 Vu B, et al. JHOP. 2011;1(2). Accessed from: http://jhoponline.com/jhop-issue-archive/2011-issues/june-vol-1-no-2/14266-top-14266 A High-Risk Population Over 25 million oral doses administered annually Error rate: 8.1 errors per 100 clinic visits A 2006 survey of US cancer centers found: 1 in 4 centers have standard safeguards 1 in 5 have measures to monitor safe administration and monitoring Weingart SN, et al. BMJ. 2007;334:407-409 Gandhi TK et al. Cancer. 2005;104:2477-2483 Walsh KE, et al. J Clin Oncol. 2009;27:891-896 Weingart SN, et al. Cancer. 2010;116:10:2455-2464 9 Image available from: http://www.untamedscience.com/science/wp-content/uploads/2013/10/boat-with-wave2.jpg Areas of Vulnerability American Society of Health-System Pharmacists (ASHP) Guidelines on Preventing Medication Errors with Chemotherapy and Biotherapy Administration (56%) and ordering (36) were the most common phases where errors occur The exact rate of errors with oral chemotherapy is not well studied The routine use of safety systems is not used for oral chemotherapy 10 Goldspiel B, et al. ASHP Council on Pharmacy Practice. 2014: 231-256 Image available from: http://saimg-a.akamaihd.net/saatchi/685505/art/3775087/2844971-WWUDPNBS-7.jpg Institute for Safe Medication Practices (ISMP) Error Report Organizations focus robustly on safety of parenteral oncology agents, but inadvertently omit oral chemotherapy Report: A 60 yo female who took the equivalent of 3 cycles of oral lomustine therapy, thinking the pharmacy only dispensed one dose (450 mg dispensed instead of 150 mg), leading to death 5 other cases since 1977 reported with lomustine 11 Accessed from: https://www.ismp.org/newsletters/acutecare/showarticle.aspx?id=84 ISMP Action Plan Recommendations Prescribers: Nurses: Specify single doses Reinforce education (Patient counseling) Be specific with patients (Patient counseling) Insurers: Provide written instructions Pay for a single month supply only Pharmacists: Manufacturer: Provide alerts (e.g. “Single dose Enhance label warnings in the only”) package insert Only dispense a single dose FDA and Manufacturer: Provide patient counseling Require a mandatory medication Supply leaflets guide Enhance Labeling Fill in community pharmacies (Unless patient counseling can occur) 12 Accessed from: https://www.ismp.org/newsletters/acutecare/showarticle.aspx?id=84 National Cancer Institute (NCI) Survey A questionnaire investigating the use of oral chemotherapy Received 42 completed questionnaires from 42 of 54 eligible NCI cancer centers 29 centers used handwritten prescriptions Organizations did not require compulsory requirements on the prescription and there is a lack of standardization Only 1/3 required written informed consent 26 centers have a nurse or pharmacist review oral therapies during an infusion appointment Estimated 42% of patients decline a pharmacist consultation No consensus for the safe practice of oral chemotherapy 13 Weingart S, et al. BMJ. 2007;334(7590):407 Medication Errors Involving Oral Chemotherapy Weingart et al. Purpose To investigate errors in prescribing, dispensing, administration and monitoring of oral chemotherapies Design Combination of literature reports and voluntary reporting Population Pubmed, Google, LexisNexis, USP, Dana Farber Harvard Cancer Center, 14 members of the Comprehensive Cancer Center Consortium for Quality Improvement, incident reports, pharmacy intervention data, and prompted clinician reports 14 Weingart SN, et al. Cancer. 2010;116:10:2455-2464 Medication Errors Involving Oral Chemotherapy: Results Medication Error Adverse Drug Near Miss Error with Low Event (%) (%) Risk of Harm (%) Wrong or extra dose (N=197) 35 (17.8) 137 (69.5) 25 (12.7) Wrong drug (N=69) 17 (24.6) 48 (69.6) 4 (5.8) Wrong no. of days supplied (N=56) 22 (39.3) 30 (53.6) 4 (7.1) Missed dose or nonadherence (N=51) 9 (17.6) 12 (23.5) 30 (58.8) Failure to check treatment parameters (N=32) 1 (3.1) 31 (96.9) 0 Wrong instructions (N=17) 3 (17.6) 11 (64.7) 3 (17.6) Wrong frequency (N=13) 1 (7.7) 12 (92.3) 0 Incomplete prescription (N=13) 0 9 (69.2) 4 (30.8) Wrong time/delay (N=12) 2 (16.7) 1 (8.3) 9 (75) Protocol breach (N=12) 1 (8.3) 7 (58.3) 4 (33.3) Wrong patient (N=11) 2 (18.2) 8 (72.7) 1 (9.1) Order system error (N=10) 0 7 (70) 3 (30) Dispensing error (N=9) 3 (33.3) 6 (66.7) 0 Other (N=6) 3 (50) 3 (50) 0 15 Weingart SN, et al. Cancer. 2010;116:10:2455-2464 Medication Errors Involving Oral Chemotherapy: Conclusions Majority of events were near misses Most commonly seen wrong or extra dose, wrong drug, wrong number of days supplied, and missed dose or nonadherence Ordering of medications (N=117) accounted for most dose errors (59.4%%), followed by administration errors (27.4%), with dispensing errors being the least leading cause (13.2%) Results subject to reporting bias Selection bias (Large cancer centers>community oncology population) Lacks number of doses dispensed to estimate event rates 16 Weingart SN, et al. Cancer. 2010;116:10:2455-2464 Interventions to Improve Oral Chemotherapy Safety and Quality JAMA Oncology summary of peer-reviewed and gray literature on interventions to improve oral chemotherapy Limitations in the body of literature including inconsistent outcome definitions and primary outcome statistical testing Interventions focused on education and remote telephone-based monitoring following initiation likely results in lower toxicity profiles E-health has not shown improvements in outcomes at this time A framework and standardized outcome definitions are needed to evaluate interventions improving oral chemotherapy delivery 17 Zerillo JA, et al. JAMA Oncology. 2017. Published Online. Available at: http://jamanetwork.com/journals/jamaoncology/fullarticle/2629957 The Journey So Far… 18 Image available from: https://img.buzzfeed.com/buzzfeed-static/static/2015-10/28/3/campaign_images/webdr04/climbing- mount-everest-everything-you-need-to-know-2-26703-1446016282-6_dblbig.jpg Specialty Pharmacy Definition