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 IARC3. Teratogenicity or fertility impairment in animal studies or in treated patients4. Evidence of serious organ or other toxicity at low doses in animal models or treated patients.

Historical Background

Mustard gas development WWI

Alkylating agents used clinically 1940's

Regular part of cancer treatment 1960's

Second malignancies reported 1970's

Developmental Toxicity and Genotoxicity of Some Common Anticancer Agents

Developmental Toxicity Genotoxicity Animal

Drug Class T E Human PM CEAlkylating 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 CEAntimetabolites 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

OUTCOME

Year Author Population Birth Defect

Fetal Loss

Other

1985 Hemminki Onc Nurses * -

1985 Selevan Onc Nurses *

1986 Taskinen Pharm Mfgr.

+

1987 Rogers Onc Nurses

*

1988(a) McDonald RNs + MDs

*

1988(b) McDonald RNs + MDs

-

1990 Stucker Onc Nurses *

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

OUTCOMEYear Author Population Birth

Defect Fetal Loss

Other

1992 Skov Onc Nurses + - + Ectopic preg.

1993 Stucker Onc Nurses + LBW, - SGA

1993 Saurel-Cubizolles

OR/Onc Nurses

* Ectopic preg.

1995 Shortridge Onc Nurses

* Menstrual dysf.

1997 Valan is Pharm + RNs

* Infertility (F);

+ (M)

1999 Valanis Rn, Pharm (M+F)

* (F);

+ (M)

1999 Peelen Onc Nurses/Prep

-/* - +/* LBW

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 Pathway in Life ofthe Drug

Populations Affected Numbers SIC/OES

A) DrugDevelopment/Manufacturing

Manufacturing PersonnelR & D Personnel

212,000 199,500

2830 8731

B) Transport/Distribution TransportersDrug Distributors

184,597 197,702

4210 5722

C) Healthcare Facility Pharmacy

PharmacistsPharmacy Techs

174,540 145,430

3251732519

D) Drug Administration Hospital-based Registered NursesOutpatient Clinic-based

2,000,0001,600,000

32502 8011

E) Home Care Home Care 925,000 8082

F) Waste Stream Issues-Patient Waste-Chemical contaminatedequipment, tubing, packaging, etc.

Hospital/clinic/home Nursing Aides/orderlies/attendants- Spill Responders- Family

1,255,210 66008

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 40ºC5-FU 1.4 2.0 3.9CP 3.3 4.4 9.0IF 0.96 1.05 1.2CIS 1.8 1.9 3.1ETOP 2.6 2.65 3.8BCNU 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 YearOSHA 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

New InitiativeNIOSH 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 ParticipantsCarmel 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 toreview 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.

Three Sub-groups

Engineering Controls

Work-Practices

Personal Protective Equipment

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