Hazardous Medicines: Current Issues & Future Challenges

1. Hazardous Medicines:Current Issues & Future Challenges Graham Sewell Professor of Clinical Pharmacy, Kingston University and Assistant Director of Pharmacy, Plymouth Hospitals Trust

2. NIOSH Definition of Hazardous Drugs Carcinogenicity Teratogenicity or other developmental toxicity Reproductive toxicity Organ toxicity at low doses Genotoxicity Structure and toxicity that mimic existing hazardous drugs (NIOSH, 2004)

3. Presentation Outline: Focus on Antineoplastic Drugs • Evidence of risk from cytotoxics: Questions………….. • Risk of cytotoxic contamination in workplace? • Risk of equipment/protection failure? • Possible health risk if exposed? • MAB’s A new risk? • Management of risk: Guidelines

4. Risk of Cytotoxic Contamination Is there any risk? If so, where does risk come from? What is the evidence? What are the implications?

5. Surface Contamination of Primary Packaging Liege Study: Surface of 90 vials 5-FU tested, 3 suppliers 27/90 – 5-FU above LOD (0.3ng) but below LOQ (1ng) 3/90 – 5-FU above LOQ (4.8-18.1ng/vial) Delporteetal EHP (1999) 5 (3) 119-121

6. Favieretal: External Contamination of Vials Vials of 5-FU, Etoposide, Ifosfamide, Cyclophosphamide, Doxorubicin, Docetaxel. 100% had contamination on outer surfaces Contamination/vial ranged 0.5 – 2500ng Differences between manufacturers Favieret al: J OncolPharm Practice (2003), 9, 15-20

7. Surface Contamination on Pharmacy Pre-filled Syringes Contamination: 5-FU 500mg/20ml syringe - 8/35 syringes (23%) contaminated - 3/15 blind-hubs (20%) contaminated Maximum contamination = 79ug LOD = 0.5ug

11. Preparation & AdministrationAreas: Surface Contamination Six US/Canadian centres studied Contamination detected in 75% pharmacy and 65% administration areas Pharmacy; highest levels on work surface and airfoil of BSC and floor in front of BSC Clinic; highest levels on floor by bed Connor etal, Am J H-S Pharm (1999),56,1427

13. Isolators: Total Protection? Simulation in aseptic clean room, Kingston University Experienced technicians, 25 batches over 4 days Sample before and after cleaning Validated wipe-sampling of isolator gloves, sleeve, base, hatch, doors, trays etc and products leaving isolator

14. Preparation Schedule Day & Session Drug Volume Syringe Size Number of Batch (ml)(ml)Units Day 1 Session 1 CP, 150mg 7.5 10 10 1 CP, 500mg 25 60 10 2 EPI, 15mg 7.5 10 15 3 Day 1 Session 2 EPI, 50mg 25 60 10 4 EPI, 75mg 37.5 60 1 5 MTX, 15mg 0.6 3 10 6 MTX, 200mg 500 500ml bag 1 7 Day 2 Session 1 CP, 200mg 10 10 10 8 EPI, 50mg 25 50 10 10 EPI, 40mg 20 20 10 11 Day 2 Session 2 MTX, 20mg 0.8 3 10 9 MTX, 20mg 0.8 3 10 12 MTX, 40mg 1.6 3 1 13 Day 3 Session 1 CP, 400mg 20 20 10 14 CP, 500mg 25 60 10 15 EPI, 20mg 10 10 10 16 EPI, 50mg 25 60 10 17 Day 3 Session 2 MTX, 100mg 500 500ml bag 1 18 MTX, 40mg 1.6 3 1 19 Day 4 Session 1 CP, 400mg 20 20 l 10 20 CP, 500mg 25 60 10 21 EPI, 30mg 15 20 10 22 EPI, 40mg 20 20 10 23 Day 4 Session 2 MTX, 7.5mg 0.7 3 10 24 MTX, 40mg 1.6 3 1 25

15. Epirubicin: Location and Amount Amount of EPI Recovered from Isolator Surfaces (ng/ml)

16. Cyclophosphamide: Location and Amount Amount of CP Recovered from Isolator Surfaces (ng/ml)

17. Methotrexate: Location and Amount Amount of MTX Recovered from Isolator Surfaces (ng/ml)

18. Surface Contamination of Syringes: Number testing +ve Period 1 Period 2 Batch EPI MTX CP EPI MTX CP EPI batches: 4 10 1 07 0 0 169 0 00 3 0 22 10 1 0 10 1 4 MTX Batches: 12 0 1 0 0 0 0 24 1 1 0 10 3 0 CP Batches: 2 0 0 0 0 0 0 8 6 0 2 3 0 0 14 9 1 0 0 0 0

19. Cross-Contamination with Biological Agents: A Real Risk? “Meningitis due to iatrogenic BCG infection in 2 immunocompromised children” Stone M et al N Engl J Med, 1995, 333, 561

20. Closed System for Cytotoxic Handling

21. Summary: Risk of Contamination Risk isreal High frequency, low amounts Clear evidence Contamination arises from drug vials, manipulation of drugs, isolator surfaces Products leaving isolators are contaminated

22. Risk of Equipment and Protection Failure • Isolators become contaminated and contaminate product. Can we clean isolators? • Isolators leak • How effective is Personal Protective Clothing (PPE)? Are they likely to fail to protect? • Gloves? • Gowns?

24. Cleaning Effectiveness: No. Wipes to Remove Drug (<LOD)

25. PPE : Are Gowns and Gloves Effective ? Penetration study on 6 protective gowns - 2/6 allowed penetration of 10 and 4 drug solutions over a 1 min test period - quality & comfort varied between gowns Harrison & Kloos J OncolPharmPract (1999) 5(2), 61-66

26. Permeability of Gloves • Connor , Am J H-S Pharm. (1999),56,2450 - Nitrile, latex, polyurethane and neoprene gloves tested against 18 antineoplastics - Permeation (>1%) occurred in 4/864 in 30 minutes - Practice conditions are different to test situation

27. Possible Health Risks of Antineoplastic Drugs Are they real ? What is the evidence ? Is the evidence too difficult to obtain ?

28. Carcinogenicity of Cytotoxic Drugs International Agency for Research on Cancer 11 agents and 2 combined therapies listed as human carcinogens (Group 1) 12 agents listed as probable human carcinogens (Group 2A) 11 agents listed as possible human carcinogens (Group 2B)

29. Cytotoxics in Pregnancy : Riskof Low Birth Wt / Birth Defects P. Scheepers , Nijmegen : Oncology nurses; 229 live births. Reference group; 956 live births. Activity Odds Ratio Low Birth Wt. Cong. def. Caring/Nursing 1.8 1.4 Admin. chemo 1.4 1.8 Prep. + Admin. 16.7 5.1

30. Pregnancy Category D or X Drugs in Current NIOSH Alert

31. Reproductive Outcomes (Health Care Workers)

32. Antineoplastic Drugs in Breast Milk • Detected in breast milk • Cyclophosphamide • Ifosfamide • Cisplatin • Doxorubicin • Fluorouracil • Methotrexate • Gemcitabine • Not Recommended for nursing mothers • Busulfan • Chlorambucil • Thiotepa • Dactinomycin • Epirubicin • Ara-C

33. American Society of Health-System Pharmacists Guidelines (2006) “Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated,staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities, if they so desire.In general, these policies should encourage personnel to solicit recommendations from their personal physicians regarding the need for restricted duties. In the case of personnel activelytrying to conceive or father a child, a similar policy should be considered, and a specific time period (e.g., three months) should be agreed upon. Legal counsel should be sought when establishing policies.”

34. Oncology Nursing Society Guidelines (2005) “Allow employees who are pregnant, actively trying to conceive, or breast-feedingor who have other medical reasons for not being exposed to cytotoxic agents to elect to refrain from preparing or administering those agents or caring for patients during their treatment with them.”

35. HSE Guidelines “Employers must conduct a specific risk assessment after receiving the Med 3 [Medical Statement] and should take into account any medical advice you have been given.If risks are identified, which go beyond the level of risk found outside the workplace, but cannot be removed, employers should adjust the woman’s working conditions or hours. If there is still a risk, she must be offered suitable alternative work or if that is not possible,suspended on full payfor as long as is necessary to protect her and her child’s health.”

36. “New” Risk Factorsin Cytotoxic Handling Centralisationofhandling(andrisk) Increasingcytotoxicuse Newdrugdeliverysystems Increasedoutpatient / hometherapy Newdrugpresentations, oral doses Use in non-malignant disease Newagents – Targeted therapies

37. Trastuzumab

38. Monoclonal antibodies: Risk issues Allergic and immunogenic reactions “Cytokine storm” E.g. TGN1412 Cross-reaction with important proteins Complement-mediated cytotoxicity Handling risk linked to NPSA 20 risk Langford etalHospital Pharmacist (2008) 15, 60-63 Debate: Hospital Pharmacist (2008) 15, 138-139

39. Conclusions • Evidence of risk of • a) contamination and • b) adverse health effects . • Risks with new & biological agents requires greater understanding and research. • Use simple, practical methods of control. • Evaluate new technologies e.g. Closed systems • Recognise limitations of equipment and procedures (e.g. cleaning) • Implement simple risk management and validate

40. Key Information Sources International Society of Oncology Pharmacy Practitioners Standards. www.isopp.org NIOSH Alert www.cdc.gov/niosh MARCH Guidelines www.marchguidelines.com Contact:G.J.Sewell@kingston.ac.uk