update on safe handling of hazardous drugs: stakeholder activities melissa a. mcdiarmid, md, mph...
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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
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
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.
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