Update on Safe Handling of Hazardous Drugs: Stakeholder Activities Melissa A. McDiarmid, MD, MPH August 1, 2002

ASHP Hazardous Drug Criteria 1. Genotoxicity (i.e., mutagenicity and clasto- genicity in short-term test systems) 2. Carcinogenicity in animal models, in the patient population, or both as reported by IARC 3. Teratogenicity or fertility impairment in animal studies or in treated patients 4. Evidence of serious organ or other toxicity at low doses in animal models or treated patients.

Historical Background

Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents Developmental Toxicity Genotoxicity Animal Drug Class T E Human PM CE Alkylating Agents BCNU + + + + Busulfan + + + + Chlorambucil + + + + + Cyclophosphamide + + + + + Ifosfamide + + + + + Nitrogen Mustard + + + + + Thiotepa + + + Cis-diaminedichloroplatinum + + + Antibiotics Actinomycin + + + + Adriamycin + + Bleomycin + + Daunomycin + + + (+) = effect seen; (-) = no effect seen. (T)=Teratogenic; (E)=Embryotoxic, (PM)=Point Mutation, (CE)=Chromosomal Effects

Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents Developmental Toxicity Genotoxicity Animal Drug Class T E Human PM CE Antimetabolites Cytosine arabinoside + 5-Fluorouracil + + + + 6-Mercaptopurine + + + + + Methotrexate + + + + + Mitotic Function Vincristine + + + - + Vinblastine + + + - + Taxol + + + + Miscellaneous DTIC (Dacarbazine) + + + Procarbazine + + + ± + Topoisomerase II Function Etoposide* + + + + (+) = effect seen; (-) = no effect seen. (T)=Teratogenic; (E)=Embryotoxic, (PM)=Point Mutation, (CE)=Chromosomal Effects *Data summarized from Sorsa M, Hemminki K, Vainio H. Occupational exposure to anticancer drugs: potential and real hazards. Mutat Res 1985;154:135-149. Updated by McDiarmid, MA. Antineoplastics, Anesthetic Agents, Sex Steroid Hormones in Paul, M Occupational and Environmental Reproductive Hazards, 1993.

Severity of the Hazard Hazardous Drugs are: 11 of 70-odd IARC Group I Carcinogens 8 of Group 2A; and 7 of Group 2B Well documented reproductive and developmental toxicants in animals and humans (Alkylating Agents, Antimetabolites); some male-mediated Associated with biologically plausible health effects in studies of exposed populations

SUMMARY OF STUDIES OF ADVERSE REPRODUCTIVE OUTCOMES IN WORKERS EXPOSED TO ANTINEOPLASTIC DRUGS Key: (+) = effect seen, (-) = no effect seen, (*) = statistically significant effect seen (F) = female; (M) = male; (LBW) = low birth wt; (SGA) = small for gestational age.

SUMMARY OF STUDIES OF ADVERSE REPRODUCTIVE OUTCOMES IN WORKERS EXPOSED TO ANTINEOPLASTIC DRUGS Key: (+) = effect seen, (-) = no effect seen, (*) = statistically significant effect seen, (F) = female; (M) = male; (LBW) = low birth wt; (SGA) = small for gestational age.

Exposure Opportunity 1,250,000 new cancer patients in US (ACS) in 2000; 500,000 will die Use of drugs for non-malignant disease (RA, SLE) Anti-viral agents for HIV treatment and other viral illnesses Investigational (IND) Drug Development/Clinical Trials

Exposure Opportunities in “Life Cycle” of Hazardous Drugs

SOURCES OF CONTAMINATION Contaminated vials Drug preparation and administration Leaks Spills Drug relocation Spread of spills BSC/HVAC

ROUTES OF EXPOSURE Dermal Oral Inhalation Particulates (droplets, dusts) Vapors

SURFACE CONTAMINATION SESSINK ET AL, 1992a CP, 5-FU, METH SESSINK ET AL, 1992b CP, 5-FU, METH McDEVITT ET AL, 1993 CP PETHRAN ET AL, 1998 CP, IF MINOIA ET AL, 1998 CP, IF CONNOR ET AL, 1999 CP, 5-FU, IF RUBINO ET AL, 1999 5-FU, METH,CY, GC SESSINK, ET AL, 1999 CP, 5-FUFU

AIR SAMPLING (PARTICULATES) SESSINK ET AL, 1992a METH/CP/IF SESSINK ET AL, 1992b METH/CP/ 5-FU McDEVITT ET AL, 1993 CP PETHRAN ET AL, 1998 CP MINOIA ET AL, 1998 CP/IF

VIAL CONTAMINATION SESSINK ET AL, 1992b CP, METH HEPP & GENTSCHEW, SEVERAL 1998 AGENTS PETHRAN ET AL, 1998 CP,IF DELPORTE ET AL, 1999 5-FU

URINE ANALYSIS HIRST ET AL, 1984 CP + VENITT ET AL, 1984 PT - EVELO ET AL 1986 CP + SESSINK ET AL, 1992a CP - 1992b CP, IF + ENSSLIN ET AL 1994a PT + 1994b CP, IF + SESSINK ET AL, 1994a FU + 1994b MTX + 1994c CP + 1994d CP + PETHRAN ET AL, 1998 DOX +

CONNOR ET AL, 1999 SIX CANCER CENTERS IN U.S. AND CANADA PHARMACIES AND TREATMENT AREAS CP, 5-FU, IF BSCs, COUNTERS, CARTS, FLOORS, CHAIRS, TABLES 75 % PHARMACY AND 65 % TREATMENT AREA SAMPLES POSITIVE FOR AT LEAST ONE DRUG ADJACENT AREAS CONTAMINATED

VAPORIZATION OF ANTINEOPLASTIC AGENTS VAPOR PRESSURE* DRUG 20ºC 25ºC 40ºC 5-FU 1.4 2.0 3.9 CP 3.3 4.4 9.0 IF 0.96 1.05 1.2 CIS 1.8 1.9 3.1 ETOP 2.6 2.65 3.8 BCNU 19 46 530 SCHMIDT ET AL, 1999 *mPa

CONNOR ET AL, 2000 VAPORIZATION OF AGENTS DRUG 23ºC 37ºC BCNU + + CP + + IF + THIO + MUST + +

Existing Handling Guidelines for Hazardous Drugs Source Year OSHA 1986, 1995 American Society of Health System Pharmacists 1985, 1990 AMA Council on Scientific Affairs 1985 Oncology Nursing Society 1988

Elements of Existing Guidelines Include a Combination of Controls: Substitution Engineering Work Practices/Administrative Controls PPE Training Medical Surveillance

OSHA Hazardous Drug Document - 1995 Enlarges domain of drugs considered ASHP definition of a hazardous drug Includes agents in tablet form Aerosolized agents Hazard Communication Standard Updated Appendix with source listed Reproductive Hazards Policy

Evidence of Adherence to Guidelines Not systematically studied Poor adherence is frequently cited in individual studies in the literature Uncommonly cited by OSHA general duty clause Not consistently surveyed by JCAHO

Safe Handling of Hazardous Drugs New Initiative NIOSH Working Group on Safe Handling of Hazardous Drugs Federal Agencies (NIOSH, OSHA, NIH, FDA) Stakeholders Drug Manufactures Professional Organizations (ASHP, ONS) Home Care Providers Accreditation Bodies (JCAHO, ACHC, CHAP) Academia

Pharm Participants Carmel Pharma Abbott Laboratories Bristol Myers Squibb Amgen Inc. Glaxo Smith Klein Super Gen Eli Lilly Bochringer Ingilbeim Merck & co. Johnson & Johnson

Purpose: Gather Public Health Agencies having jurisdiction and affected stakeholders to review current handling practices of hazardous drugs in healthcare in light of new evidence suggesting current practices are not adequately proactive; recommend work practice changes and training needs required to more adequately protect HCWs; identify research needs; and commit to work group.

Personal Protective Equipment Three Sub-groups Engineering Controls Work-Practices Personal Protective Equipment

“Universal Precautions” Consider a new type of “Universal Precautions” for handling these agents Performance-based Includes aspects of existing guidelines and those to be added by working group

FUTURE NIOSH ALERT HARMONIZATION OF GUIDELINES ADDITIONAL RECOMMENDATIONS

www.OSHA.gov/outreach/technical links/ controlling occupational exposure to hazardous drugs