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) Delporte etal EHP (1999) 5 (3) 119-121

6. Favier et al: 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 J Oncol Pharm Practice (2003), 9, 15-20 Favier et al: J Oncol Pharm Practice (2003), 9, 15-20

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

11. Preparation & Administration Areas: 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 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 1CP, 150mg 7.5 10101 CP, 500mg 25 60102 EPI, 15mg 7.5 10153 Day 1 Session 2EPI, 50mg 2560104 EPI, 75mg 37.56015 MTX, 15mg 0.6 3106 MTX, 200mg 500500ml bag 17 Day 2 Session 1CP, 200mg 1010108 EPI, 50mg 25501010 EPI, 40mg 20201011 Day 2 Session 2MTX, 20mg 0.8 3109 MTX, 20mg 0.8 31012 MTX, 40mg 1.6 3113 Day 3 Session 1CP, 400mg 2020 1014 CP, 500mg 2560 1015 EPI, 20mg 1010 1016 EPI, 50mg 2560 1017 Day 3 Session 2MTX, 100mg 500500ml bag 118 MTX, 40mg 1.6 3 119 Day 4 Session 1CP, 400mg 2020 l1020 CP, 500mg 2560 1021 EPI, 30mg 1520 1022 EPI, 40mg 2020 1023 Day 4 Session 2MTX, 7.5mg 0.7 31024 MTX, 40mg 1.6 3125

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

18. Surface Contamination of Syringes: Number testing +ve Period 1 Period 2 Period 1 Period 2 Batch EPI MTX CP EPI MTX CP EPI batches: 4 10 1 0 7 0 0 4 10 1 0 7 0 0 16 9 0 0 0 3 0 16 9 0 0 0 3 0 22 10 1 0 10 1 4 22 10 1 0 10 1 4 MTX Batches: 12 0 1 0 0 0 0 12 0 1 0 0 0 0 24 1 1 0 10 3 0 24 1 1 0 10 3 0 CP Batches: 2 0 0 0 0 0 0 2 0 0 0 0 0 0 8 6 0 2 3 0 0 8 6 0 2 3 0 0 14 9 1 0 0 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 is real 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) Test Detergent 5-FU (WFI) 5-FU (N/S) CP (WFI) CP (N/S) DOX (WFI) DOX (N/S) WFI131111 Criti-Klenz111122 CIP 150111133 CIP 100111122 Renu -Klenz111111 NpH-Klenz111111 Cage-Klenz111111 CIP 220111111 CIP 200 111111 IMS111111

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 - 2/6 allowed penetration of 10 and 4 drug solutions over a 1 min test period - quality & comfort varied between gowns - quality & comfort varied between gowns Harrison & Kloos J Oncol Pharm Pract (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) 11 agents and 2 combined therapies listed as human carcinogens (Group 1) 12 agents listed as probable human carcinogens (Group 2A) 12 agents listed as probable human carcinogens (Group 2A) 11 agents listed as possible human carcinogens (Group 2B) 11 agents listed as possible human carcinogens (Group 2B)

29. Cytotoxics in Pregnancy : Risk of Low Birth Wt / Birth Defects P. Scheepers, Nijmegen : Oncology nurses; 229 live births. Reference group; 956 live births. Activity Odds Ratio Activity Odds Ratio Low Birth Wt. Cong. def. 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 USFDA Category No. Agents Definition D46 There is clear evidence of risk to the human fetus, but the benefits may outweigh the risk for pregnant women. X5 There is clear evidence that the medication causes abnormalities in the fetus. The risks outweigh any potential benefits for women who are pregnant.

31. Reproductive Outcomes (Health Care Workers) EndpointNo. Studies Pos/Total No. Significant Studies Spontaneous Abortions 4/52 Congenital malformations 3/42 Stillbirths2/20 (Dranitsaris et al, 2005)

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 actively trying 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- feeding or 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 pay for as long as is necessary to protect her and her child’s health.”

36. “New” Risk Factors in Cytotoxic Handling “New” Risk Factors in Cytotoxic Handling Centralisation of handling (and risk) Increasing cytotoxic use New drug delivery systems Increased outpatient / home therapy New drug presentations, oral doses Use in non-malignant disease New agents – 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 etal Hospital Pharmacist (2008) 15, 60-63 Debate: Hospital Pharmacist (2008) 15, 138-139

39. Conclusions Evidence of risk of a) contamination and a) contamination and b) adverse health effects. 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 www.isopp.org NIOSH Alert www.cdc.gov/niosh www.cdc.gov/niosh MARCH Guidelines www.marchguidelines.com www.marchguidelines.com Contact: G.J.Sewell@kingston.ac.uk