1

Safe Handling of

Hazardous Drugs

1.5 Contact Hours

Commercial Support Provided by:

Carmel Pharma, Inc.

Question 1

What is your primary practice setting?

A. Hospital Pharmacy

B. Long Term Care

C. Education

D. Other

2

Question 2

What is your position?

A. Pharmacy Director/Management

B. Staff Pharmacist

C. Pharmacy Technician

D. Student

. Other

Question 3

Are you familiar with the current studiesrelated to closed-system drug transferdevices?

A. Yes

B. No

C. Not Sure

3

Question 4

So far…

A. I’ve hit the jackpots.

B. I am even.

C. I’ve lost some money, but haven’t given up.

D. I don’t gamble.

. It looks like my friends and family will notbe getting any gifts this holiday season!

Program Information

• Target Audience: Pharmacistsand Certified Pharmacy Technicians

• ACPE Nos.384-000-07-024-L04-P384-000-07-024-L04-T

• 1.5 Contact Hours

• Release Date: 12/1/07

• Expires: 12/1/10

• Statements of Credit will be issuedby mail within 2 weeks.

• STAT Educational Services is accredited by theAccreditation Council for Pharmacy Education(ACPE) as a provider of continuing pharmacyeducation.

4

Contact Information

STAT Educational Services

Phone 888-247-8700

Fax 888-247-8706

E-mail mike@asyntria.com

PO BOX 683148

Houston, Texas 77268

Presentation Download Available at

www.statce.com

Learning Objectives

1. Describe the reproductive risks associatedwith exposure to chemotherapeutic agents.

2. Describe the carcinogenic potentialassociated with exposure tochemotherapeutic agents.

3. Analyze the findings from current researchand studies on closed-system drug transferdevices.

4. Present the NIOSH current recommendationsfor a medical surveillance program forhazardous drugs.

5. Describe the medical surveillance program forhazardous drugs of a community basedpharmacy.

5

Jim Jorgenson, RPh, MS, FASHP

Administrative Director for Pharmacy Services

Associate Dean for Pharmacy

University of Utah

james.jorgenson@hsc.utah.edu

What Defines a “Hazardous Drug”

1. Carcinogenicity

2. Teratogenicity or otherdevelopmental toxicity

3. Reproductive toxicity

4. Organ toxicity at low doses

5. Genotoxicity

6. Structure & toxicity profile for newdrugs that mimics existinghazardous drugs

6

Standards & Guidelines

Guidelines

• ASHP

• ONS

• ISOPP

• HOPA

• European Oncology

• NIOSH

Standards

• USP 797

• OSHA

• JCAHO

Why Do We Care?

The same mechanisms that thesedrugs employ to kill cancer cellsalso works to damage healthy cells

NIOSH Warning

Working with or near hazardousdrugs in health care settings maycause skin rashes, infertility,miscarriage, birth defects andpossibly leukemia or other cancers

7

OSHA

“Preparation, administration, and

disposal of hazardous drugs

may expose pharmacists,

nurses, physicians, and other

health care workers to

potentially significant

workplace levels of these

chemicals.”

8

Recent Concerns

• Increasing evidence of exposure

• Increasing numbers of cancerpatients

• More drug combinations

• Higher doses of drugs

• More potent drugs

• Increasing non-cancer use ofantineoplastics

• New treatment settings

Source = Thomas Connor, Ph.D., NIOSH

Presence of Hazardous Drugs

in the Workplace

• Numerous published studiesdemonstrating the presence ofhazardous medications in theworkplace

• Multiple studies demonstrating thathazardous drugs are present in theurine of healthcare workers includingpharmacists and technicians

9

Adverse Effects

Patients =

High doses with limited number ofdrugs over a defined time period.

Healthcare Workers =

Low doses of multiple drugs overlong periods of time

Acute Effects

• Nausea

• Vomiting

• Headache

• Dizziness

• Hair Loss

• Mucosal Sores

• Liver Damage

10

Long Term Effects

• Reproductive

• Developmental

• Genetic

• End Organ Damage

• Cancer

Reproductive Risks

• Numerous peer reviewed studies thatclearly establish a direct cause andeffect relationship between exposureto cytotoxic agents and adverseeffects

• Statistically significant differencesbetween healthcare workers exposedto these agents and the generalpopulation in terms of: spontaneousabortions, infertility, premature labor

11

Occupational Exposure to

Antineoplastic Agents

• Kaiser Permanente Center for HealthResearch

• 7,094 pregnancies of 2,976 pharmacyand nursing staff studied

• Exposure of mother to handlingantineoplastic agents duringpregnancy was associated with asignificant increased risk forspontaneous abortion and stillbirth

Journal of Occupational & Environmental Med

Vol.41; 8: 632-638

Developmental Effects

• Numerous peer reviewed studiesdemonstrating a statisticallysignificant difference in low-birthweight infants, birth defects andlearning disabilities in offspring ofhealth care workers exposed tohazardous meds during theirpregnancy

12

Teratogenicity

• Conflicting opinion on exposureduring 2nd and 3rd trimesters

• Greatest danger during 1st trimester• Hemminki case control study of

Finish oncology nurses activelyhandling chemotherapy during1st trimester

• Demonstrated statistically significantincrease in riskfor malformations

• Odds ratio of 4.7 (p=0.02)

Hemminki K, Kyyronen P, Lindbohm ML. J Epidemiol Community Hlth1985

Cancer Risk

• No question that given enoughexposure these agents can causecancer

• IARC designation

• Sessink cancer risk model forcyclophosfamide

13

Carcinogenic Potential

• IARC Group 1 Human Carcinogens(102 chemical entities)10 drugs and 2 combination therapies;cyclophosphamide, azothiaprine, busulfan, thiotepa,tamoxifen, etoposide

• IARC Group 2A Probable Carcinogens (68 chemicalentities)9 drugs; azacitadine, carmustine, CCNU, cisplatin,doxorubicin, nitrogen mustard

• IARC Group 2B Possible Carcinogens (245 chemicalentities)

• 10 drugs; dacarbazine, daunoribucin, bleomycin,mitomycin, mitoxantrone

Cancer Development

• Numerous case studies

• Significant increase in leukemia notedamong oncology nurses in the Danishcancer registry(Br J Ind Med 49:855-61)

• 39 YO pharmacist with papillarytransitional cell carcinoma(J Nat Can Inst 85(13):1089-91)

• 39YO vetrinarian with atypcial thyroidcancer

14

Genetic Effects

• Genotoxic effects noted inboth patients and healthcareworkers

• DNA single strand breaks

• Chromosomal aberrations

• Length of exposure mostsignificant factor

Demonstrated Genotoxicity

• Significant increase (2.5X) in chromosomalaberrations in nurses and pharmacy techs handlingchemotherapy compared to healthy subjects nothandling chemo (Cavaloa Abstract 2005–Publicationpending)

• Examined two oncology nurse groups, one usingPPE and one not vs. a control group. Statisticallyhigher rate of sister chromatid exchange in theunprotected group when compared to both thecontrol and protected group (p<0.001) Brumen Am JIndust Med 30:67071, 1996

• Examined lymphocyte DNA damage in oncologynurses compared to controls and demonstratedincreased DNA damage secondary to cytotoxic drughandling Yoshida, J Occup Health, 48:517-22, 2006

15

Summary

• Cancer chemotherapy presents a clearhealth hazard for healthcare workers

• Both acute and long term effects of thesemedications should be considered

• Clear cut safety precautions based onsound medical evidence should beestablished in the work place

Question 1

The National Institute of Safety andOccupational Health includes all of thefollowing elements in it’s definition of ahazardous drug except:

A. Carcinogenicity

B. Flammability

C. Teratogenicity

D. Genotoxicity

16

Question 2

Which of the following drugs has beenclassified by the International Agency forResearch on Cancer as Group I, a knownhuman carcinogen?

A. Mitomycin

B. Doxorubicin

C. Cyclophosphamide

D. Bleomycin

Susan M Spivey, DDS,PharmD

Ambulatory Treatment Center Pharmacy ManagerUT M.D. Anderson Cancer Center

sspivey@mdanderson.org

17

Routes of Exposure

• Dermal- direct contact w/drugsor contaminated surfaces

• Oral Ingestion – food, gum,hand to mouth

• Inhalation

- Particulates (droplets, dusts)

- Vapors

• Injection – sharps , breakage

Surface Contamination Studies

• 27 Published studies

• All studies detected measurablelevels of at least one drug

• Contaminated areas included:biological safety cabinets, floors,counters, IV bags, keyboards,gloves, transport containers,patient tables, chairs, wastecontainers

18

Surface Contamination Studies

• In 1999, Connor et al. demonstratedsurface contamination withcyclophosphamide, ifosfamide andfluorouracil in pharmacy and patienttreatment areas in three hospitals inthe U.S. and three in Canada

Surface Contamination Studies

• 75 % of pharmacy and 65 % ofpatient treatment areas werecontaminated with at least oneof the three drugs

• Drugs were detected in adjacentareas where drugs were nothandled

(Connor et al, 1999)

19

Air Sampling Studies

• 16 Published studies

• Particulate collection on paper orglass filters

• Low percentage of samples containeddrugs

• Drug levels were usually low

Fluorescein Study

Conventional Needle/ SyringeTechnique

vs

Utilizing PhaSeal

(S M Spivey, T H Connor 2003)

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Fluorescein Study

• Fluorescent dye

• Inspected with UV light

• Evaluated fluorescein release into thework environment

Fluorescein Study

Evaluated

-Drug Reconstitution

-Drug Transfer ( vial- IV bag)

-Drug Administration/Disconnection

21

Drug Reconstitution With Needle and Syringe

Drug Preparation with PhaSeal®

22

Drug Transfer with Needle and Syringe

Drug Transfer with PhaSeal®

23

I.V. Push with Needle and Syringe

I.V. Push with PhaSeal®

24

Needle/Syringe vs PhaSeal®

Using Fluorescein

Release of fluorecein

Closed

Needle/Syringe System

Reconstitution YES NO

Drug Transfer YES NO

Vial-Bag Administration YES NO

I.V. Push YES NO

Fluorescein Summary

• All phases of the conventionalneedle/syringe technique resulted inrelease of drug into the environment

• Most surface contamination was 1-4mm in diameter, but some wereconsiderably larger.

25

Summary

• Total of 75 manipulations

• No fluorecein release was detectedwith PhaSeal.

2006 Utah Protocol

University of UtahEvaluation of Vial Transfer Devices for

Containment of Hazardous Drug Vapors

(C Au, J A Jorgensen, B Smith 2006)

26

Objective

Examine commercially availabledrug transfer devices anddetermine which products meetthe NIOSH definition of a closed-system drug transfer device(CSTD).

NIOSH Definition

“A closed-system drug transfer devicemechanically prohibits the transfer ofenvironmental contaminants into thesystem and the escape of hazardousdrugs or vapor concentration outsidethe system”

27

Methods

• Evaluated five systems

– B.Braun OnGuard System withTevadaptor components—Vial adaptor

– Alaris Smart Site® Vented VialAccess Device

– PhaSeal ® Protector 50 andInjector Luer lock

– Chemoprotec Spike® (Codan)

– Chemo Mini Spike Plus™Dispensing Pin

Methods

• Titanium tetrachloride

– Simulates the escape of cytotoxicvapors

– Generates visible smoke when incontact with air

• Titanium tetrachloride added to eachvial (3 ml) and crimp sealed

• Each vial was spiked with eachindividual product

28

Methods

• 60 ml syringe with 50 ml airwas attached to each device

• Air was injected over 10 seconds

• Photographs and videos were takento record any escape of titanium fromeach product

• Filters were tested for potentialdamage from hydrochloric gasor titanium dioxide

Engineering Controls

Closed systems drug transfer device

Mechanically prevent the transfer ofenvironmental contaminants into thesystem and the escape of drug or vaporout of the systems.

Phaseal

Many more competitors in the market

Not a substitute for ventilated cabinets

29

2006 Utah Protocol

Results

• The PhaSeal® System was the onlysystem to prevent the release oftitanium smoke from the closedsystem drug transfer device

• PhaSeal® was the only device thatmet the NIOSH definition of a closed-system drug transfer device.

30

Parallel Fluoroscein Studies

Conducted byU. T. M. D. Anderson Cancer Center

and The University of Utah

S M Spivey, J A Jorgenson 2007

Objective

Evaluate the potential to releasefluorescein into the environment in thepreparation and administration phases.

• B.Braun OnGuard Systemw/Tevadaptor components

• Cardinal/Alaris System

• PhaSeal® System/Carmel Pharma

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Methods

Preparation Phase

• 0.05% Fluorescein dye 15ml/20mlvial

• 5 mls withdrawn and 1ml reinjectedinto vial

• Vial adaptor and syringecomponents were disengaged,observed and photographed underuv light and touched to a 4 x 4gauze.

Methods

Administration Phase

• Simulation of a 7 ml IV push

• Observing the syringe adaptors andIV port device for each product

32

Alaris Smart Site®/Texium™

(Cardinal Health)

Alaris Smart Site®/Texium™

(Cardinal Health)

33

Touch Test - Alaris Smart Site®/Texium™

(Cardinal Health)

BBraun OnGuard System Tevadaptor™ Vial

Adaptor & Tevadaptor™SSyringe Adaptor

(Teva Medical, Ltd)

34

BBraun OnGuard System Tevadaptor™ Vial

Adaptor & Tevadaptor™SSyringe Adaptor

(Teva Medical, Ltd)

Touch Test - BBraun OnGuard System

Tevadaptor™ Vial Adaptor & Tevadaptor™

Syringe Adaptor (Teva Medical, Ltd)

35

PhaSeal® Protector

(Carmel Pharma)

PhaSeal® Protector & Injector Luer

(Carmel Pharma)

36

Touch Test - PhaSeal® Protector &

Injector Luer (Carmel Pharma)

ResultsPreparation Phase

0%87%

77%Touch Test

0%67%47%Syringe

Adaptor

0%80%56%Vial Adaptor

PhaSeal®System

Cardinal/AlarisSystem

BBraunOnGuard

System

37

ResultsAdministration Phase

0%100%60%TouchTest

0%100%60%IV Port

0%80%60%SyringeAdaptor

PhaSeal® System

Cardinal/

Alaris

System

BBraun

OnGuard

System

Results

• B.Braun’sOnGuard/Tevadaptor™System and Cardinal Health/AlarisSystem showed visible fluoresceinleaks on each component duringdrug preparation and administrationphases

• PhaSeal® System showed no visiblefluorescein leakage during thepreparation and administrationphases

38

2007 Utah Protocol Update

University of UtahEvaluation of Vial Transfer Devices for

Containment of Hazardous Drug Vapors

(C Au, J A Jorgensen, B Smith 2007)

Objective

Examine commercially available drugtransfer devices and determine whichproducts meet the NIOSH definition of aclosed-system drug transfer device(CSTD).

39

2007 Utah Protocol Update

Results

• The PhaSeal® System was the onlysystem to prevent the release oftitanium smoke from the closedsystem drug transfer device

• PhaSeal® was the only device thatmet the NIOSH definition of a closed-system drug transfer device.

40

Leakproof Connection

Integrity Test

For Devices Intended for

Handling Hazardous Drugs

(J A Jorgensen 2007)

Objective

• To determine if the ICU MedicalSystem, B. Braun/Tevadaptor™System, Cardinal/Alaris System orPhaSeal® System connections areleak proof or have the potential toallow drugs to escape into theenvironment during the preparationand administration phases ofhazardous drug handling.

41

Methods

• Four transfer devices were tested

• A liquid with low pH was used as a substitute foractive drug. Litmus paper was used as pH indicator.Blue litmuspaper turns red under acidic conditions.

• Syringes were filled with fluid and injected into vialsattached to the above transfer devices. Afteraspirating back and disconnecting, the connectionsof each device were pressed against litmus paper todetect the presence of any fluid.

• Every component of each device was tested for 10 manipulations.

Clave® Vial Adaptor & Spiros™ Male

Connector (ICU Medical, Inc.)

42

B. Braun/Tevadaptor™ Vial Adaptor &

Syringe Adaptor (Teva Medical Ltd.)

Alaris SmartSite® Vented Vial Access Device

& Texium™ Male Luer (Cardinal Health)

43

PhaSeal® Protector & Injector Luer Lock

(CCarmel Pharma)

Results

• Visible leakage occurred outside ofthe components on the ICU MedicalSystem Clave® and Spiros™connections, the B.Braun/Tevadaptor™ System and theCardinal Health/Alaris System duringall manipulations.

• No leakage was observed in any ofthe manipulations with the PhaSeal®System.

44

Make Sure You Know

What You’re Getting….ASK

• If the device uses a filter to equalizethe air pressure, it is not a closedsystem

• Ask for Clinical Studies, peer reviews,or independent studies (white papersare not acceptable)

• The device must meet therequirements of closed-system drugtransfer device as defined by NIOSH

Question 1

What are characteristics of a closed-system drug transfer device?

A. Mechanically prohibits transfer ofenvironmental contaminants intothe system

B. Does not allow escape of hazardousdrugs

C. Does not allow the escape of vapors

D. All of the above

45

Question 2

What is important to know before choosing aclosed-system

drug transfer device?

A. Peer reviews, independent studies, and/orclinical studies exist on the product.

B. The product must meet the NIOSH definitionof a closed system

C. Does the device have filters that let airescape

D. All of the above

Dr. Paul J.M. Sessink, PhD

Exposure Control B.V., FounderThe Netherlands

www.exposurecontrol.nl

46

Toxicity of Antineoplastic Drugs

Acute effects

• Irritation (skin, eyes)

• Alopecia

• Nausea

• Vomiting

• Diarrhea

• Organs (liver, kidney,bladder, lung)

• Bone marrowsuppression

Delayed effects

• Reproductive effects– Spontaneous

abortions– Malformations

off-spring– Low birth weight– Prolonged time to

pregnancy• Menstrual dysfunction• Mutagenicity• Carcinogenicity

– Genotoxic/Non-genotoxic

– IARC classification

Genotoxic Carcinogens

Mechanism of Action

• Absence no-adverse-effect level supposed:

one molecule is able to induce cancer !

• Exposure has to be avoided

• Workers need to be protected

• Safety guidelines and protectivemeasures

• Monitoring of the workers

47

Council Directive European Union

Carcinogenic Compounds 28 June 1990

STRATEGY (decreasing priority)

1) replacement by a less toxiccompound

If not possible

2) reduce sources of exposure

If not possible

3) ventilation

If not possible

4) personal protection

Council Directive European Union

Carcinogenic Compounds 28 June 1990

STRATEGY FOR ANTINEOPLASTIC DRUGS

1) replacement by a less toxic compound

Impossible

2) reduce sources of exposure

Closed systems

3) ventilation

Clean rooms with BSCs

4) personal protection

Gloves, gowns, masks, specialclothes, …

48

Environmental and Biological Monitoring

Environmental Monitoring

• Measures thepresence/release of thedrug in the environment

• No information aboutuptake of the drug in thebody of the worker

• No information abouthealth-risk for theworker

Biological Monitoring

• Assessment ofuptake of the drug

in the body of theworker

• Estimation of health-risk for the worker

Monitoring Antineoplastic Drugs

Exposure Control B.V.

Environmental Monitoring

• Cyclophosphamide 0.1 ng/mlsample

• Ifosphamide 0.1 ng/mlsample

• 5-Fluorouracil 20 ng/mlsample

• Methotrexate 5 ng/mlsample

• Platin compounds (cis-platin & carbo-platin) 0.2 ng/mlsample

• Etoposide 50 ng/mlsample

• Mitomycine C 100ng/ml sample

Analysis:HPLC, GC-MSMS, Voltammetry

49

Monitoring Antineoplastic Drugs

Exposure Control B.V.

Biological Monitoring (urine)

• Cyclophosphamide 0.1 ng/mlsample

• Ifosphamide 0.1 ng/mlsample

• 5-Fluorouracil (a-fluoro-ß-alanine) 20 ng/mlsample

Analysis:GC-MSMS

Sources of Contamination

and Potential Exposure

• External vial contamination

• Spillage during preparation andadministration(handling technique)

• BSC/isolator

• Patient (urine, sweat, vomit,blood, faeces)

• Waste

• Laundry and clothing patient

50

Glove Contamination During

Preparation of Antineoplastic Drugs

19 – 1564Methotrexate

16 – 1040105-Fluorouracil

371Cyclophosphamide10

220 – 19002Methotrexate

21 – 620115-Fluorouracil

1.5 – 9.68Cyclophosphamide17

Range ( g/pair)N(pos)DrugPair of gloves

Contamination BSC

+--4

--+3

++++++2

+++1

After alcoholcleaning

Afterpreparation

Beforepreparation

Day

Drugs analyzed: cyclophosphamide - 5-fluorouracil -methotrexate

+ one drug detected++ two drugs detected+++ three drugs detected- no drugs detected

Conclusion: contamination and ineffective cleaning procedure

51

Surface Contamination with Cyclophosphamide

in Preparation Areas (ng/cm2)*Connor et al., Am J Health-Syst Pharm 1999; 56:1427-32

0.010.090.14-0.190.01-0.13

Floor entrancepreparation

room/corridor

0.01-0.020.160.52Floor entrancepreparation room

0.01-0.360.03-0.190.02Table top not forcyto preparation

0.01-0.021.771.240.15-0.310.01-2.360.11-0.16Floor centralpreparation room

0.01-0.030.051.790.05-0.550.03-2.400.05-0.32Floor under BSC

0.01-1.1614.02-14.224.74-15.320.13-6.610.05-40.130.01-2.63Table top cytopreparation/BSC

NetherlandsGermanySwedenBelgiumUSA*Canada*Description surface

Surface Contamination with Cyclophosphamide

in Administration Areas (ng/cm2)*Connor et al., Am J Health-Syst Pharm 1999; 56:1427-32

0.02-0.090.01-0.59Floor corridor/awayfrom administration

0.03-0.50Arm rest chair visitorspatient

0.01-0.07Floor toilet patients

0.090.01Top patients table

0.09-1.49Arm rest chair patient

0.01-7.370.03-0.640.01-1.00Floor near bed patient(infusion pole)

NetherlandsUSA*Canada*Description surface

52

Surface Contamination with

Cyclophosphamide in Preparation Areas

Reduced with PhaSeal*Sessink et al., submitted to Am J Health-Syst Pharm

P < 0.0001

0.030.03< 0.01-0.90< 0.01-122.2729Counter

0.010.14< 0.01-16.33< 0.01-34.7629Floor in front of BSC

0.203.860.01-17.15< 0.02-158.0026BSC airfoil

0.020.13< 0.01-5.41< 0.01-17.1930BSC surface

PhaSealStandard

techniquesPhaSeal

Standard

techniques

MedianMin-MaxNSurface

Cyclophosphamide (ng/cm2)

22 US Hospital

Pharmacies

2001-2005

Vapor Pressure Antineoplastic DrugsKiffmeyer et al., Pharm J 2002; 268:331-7

0.080.00141305-Fluorouracil

0.630.0026289Etoposide

0.360.0033261Cyclophosphamide

0.220.0018300Cisplatin

1.70.019214Carmustin

Max.

concentration

(mg/m3)

Vapor

pressure

(Pa) at

20°C

Mol.

Weig

ht

Antineoplastic

Drug

Conclusions

– Antineoplastic drugs possess a low vapor pressure

– Maximum concentrations possible by insufficient ventilation

– Protective clothes and equipment are not designed to protectworkers from vaporized antineoplastic drugs

– Additional health-risk ?

53

Cyclophosphamide (CP) in Urine of Dutch

Technicians Preparing Antineoplastic Drugs

0.1836476851-8

0.0924088

0.1014287

0.0126986

0.07683165

0.231199164

0.1864783

0.1223182

0.53665131

Mean CP

( g/day)

Number of positive

samples

Number of urine

samples

Number of

days

Technician

Cyclophosphamide (CP) in Urine of Dutch

Nurses Administrating Antineoplastic Drugs

0.8016103161-7

0.2211127

0.4252846

001425

001224

0.2321723

0.573922

4.1351221

Mean CP

( g/day)

Number of positive

samples

Number of urine

samples

Number of

days

Nurse

54

Additional Cancer Risk

Exposure to Cyclophosphamide

• Technicians

– 0.18 g CP inurine/day

– 1.4-10 extracancer cases amillion workers ayear

• Nurses

– 0.80 g CP inurine/day

– 10-50 extra cancercases a millionworkers a year

• Prohibitory risk level

– 100 extra cancercases a millionworkers a year

• Strive risk level

– 1 extra cancer casea million workers ayear

• Conclusion

strive risk level not

achieved

too high exposurelevels

Cancer Risk Level in Relation to Environmental

Contamination with Cyclophosphamide

YesYesYesNow and

thenMonitoring

YesStop

working

YesImmediately

YesAt shortnotice

NoAction

> 101.0 – 100.1 – 1< 0.1Contamination CP (ng/cm2)

> 20.2 - 20.02 – 0.2< 0.02Urine CP ( g/24 hr)

Prohibitoryrisk level

Striverisk level

55

Conclusions

• Antineoplastic drugs are spread in theenvironment during preparation, administration,patient care and waste handling

• Healthcare workers are exposed toantineoplastic drugs

• The main exposure routes are:

– Dermal uptake contact with contaminatedsurfaces

– Inhalation particles (vapors?)

• Additional cancer risk for hospital workershandling antineoplastic drugs (nurses >technicians)

• Vials are mostly contaminated

• Gloves are always contaminated

• Avoid open connections– Do not disconnect systems

Question 1

Based on the current knowledge what isconsidered to be the most importantexposure route of antineoplastic drugs forhospital workers?

A. Inhalation

B. Ingestion

C. Skin Permeation

56

Question 2

Protective gloves used for preparation ofantineoplastic drugs should be changed:

A. Once a day

B. After each shift

C. Every 2 hours

D. Every 30 minutes

Firouzan ‘Fred’ Massoomi,

Pharm.D., FASHP

Pharmacy Operations CoordinatorNebraska Methodist Hospital

Omaha, Nebraska

fred.massoomi@nmhs.org

57

Nebraska Methodist Hospital

Department of Pharmacy Services

• Scope of Department• In-patient Pharmacy Services• Home Infusion• Anesthesia Support Services• Cancer Center Infusion• Ambulatory Anticoagulation Service

• Fully automated dispensing– Pyxis, AutoMed, BAXA, McKesson, Cerner

• Bedside barcode scanning, 100%• USP <797> & NIOSH compliant work space

– Cleanroom 400 sqft; IV Workroom 380 sqft; HD room 160sqft

• 51 FTE’s, equating to 90 team members– 40 RPhs, 26 PharmTechs, 10 Interns, 4 RN’s, 3 Anesthesia Techs, 2 LPN’s

• Formal decentralized clinical services Centralized services

•• M-F; 7am to 10pm; M-F; 7am to 10pm; 24/ 724/ 7

2006 Automated Dispensing

1,004,967 Oral doses

235,742 IV Push, topicals (etc.)

2006 Sterile Compounding

285,548 Large volumes

301,902 Sterile Products

Low and medium risk

10,392 “Hazardous drugs”

Nebraska Methodist Hospital

Department of Pharmacy Services

Dispensing Statistics

58

“Workers may be exposed to a hazardous

drug at many points during its manufacturer,

transport, distribution, receipt, storage,

preparation, and administration…..Exposure

to these drugs in the workplace has been

associated with acute and short-term

reactions, as well as long-term effects”

ASHP Guidelines on Handling Hazardous Drugs

Am J Hosp Pharm 2006

“Studies have associated workplace

exposures to Hazardous Drugs with health

effects such as skin rashes and adverse

reproductive outcomes (including infertility,

spontaneous abortions, and congenital

malformations) and possibly leukemia and

other cancers”

NIOSH Alert: Preventing Occupational Antineoplastic andOther Hazardous Drugs in Health Care Settings

CDC 2004

59

Advent of Modernday chemotherapy

Loius Goodman andAlfred Gillmon use

nitrogen mustard totreat non-Hodgkin’s

Lymphoma

First review ofcarcinogenicpotential ofanticancer drugs

“The carcinogencityof anticancer drugs:

A Hazard in Man”

First case reportof occupationalexposure riskwith HDs

“Mutagenicity in the

urine of nurses

handling cytostatic

agents”

1981

First publishedguidelines forhandling HDs

“Developing guide-

lines for working

with antineoplastic

drugs”

1942 1983

American MedicalAssociationguidelines forHDs

“Guidelines for

handling parenteral

antineoplastics”

1985

Risk defined foroccupationalexposure to HDs

“Risk of handling

injectable

antineoplastic

agents”

American Societyof HospitalPharmacistsTechnicaladvisory bulletin(TAB) on handlingcytotoxic andhazardous drugs

OSHA TechnicalManual: Control-

ling occupational

exposure to HDs

Chapter 21.(OSHA instructionCPL 2-2.20B CH4)

OSHA TechnicalManual Update:Controlling

occupational

exposure to HDs

OSHA instructionTED 1-0.15ASection VI.Chapter 2

First USevaluation ofPhaSeal“Evaluation of the

PhaSeal

hazardous drug

containment

system”

USP <797>”Pharmaceutical

compounding-Sterile

preparations”

American Societyof Health-SystemPharmacistsGuidelines onhandlinghazardous drugs

1990 1995 19991976 1979 2004 2006

NIOSH AlertPreventing

occupational

exposure to

antineoplastic and

other HDs in

healthcare settings

Timeline of Significant Studies andTimeline of Significant Studies and

Guidelines for Hazardous DrugsGuidelines for Hazardous Drugs

2007

DHHS NIOSH2007-117 “Medical

Surveillance for

health care

workers exposed to

HDs”

Guidelines for Hazardous Drugs

Source Year

ASHP 1985, 1990, 2006

NIOSH Alert 2004, 2007

OSHA 1986, 1996, 1999

Oncology Nursing Society 1988, 2003

AMA Council on Scientific Affairs 1985

60

OSHA and NIOSH Standards

• Occupational Safety and Health Administration(OSHA)

– Author Agency: US Department of Labor

– US Labor Laws

• OSHA Technical Manual: ControllingOccupational Exposure to Hazardous Drugs

1999

• National Institute for Occupational Safety & Health(NIOSH)

– Authoring Agency: Centers for Disease Control

– US Practice Standards

• NIOSH Alert: Preventing OccupationalExposures to Antineoplastic and OtherHazardous Drugs in Health Care Settings

August 2004

NMH Approach to Handling

Hazardous Drugs

• Sub-committee of Hazardous Material Committeeformed in early 2005

• Representation by Nursing, Pharmacy,Human Resources, Safety, Surgery,Radiology, Performance Improvement,Employee health, House Keeping

• Goals– Address national compliance standards to

daily practices to ensure patient and employeesafety

– Compare practices to nationally approvedlabor laws and practice standards

– Conduct a Gap Analysis of policy to practice– Formally present findings– Implementation strategies

61

Process of Gap Analysis

• Initial knowledge level of key stakeholders: low

• Formal education through presentations

• Required reading of OSHA & NIOSH

• Preparation of Gap Analysis Grid to assess compliance

• Supporting documentation through policies to practice

• Practice in most cases dictated compliance

• Analysis of sites outside of Methodist Hospital

• Grid may be used as a tool for compliance

to clinics

• Site visits to two outside clinics demonstrated lack ofcompliance toOSHA and EPA regulations

Hazardous Drugs

“Pharmaceutical agents are classified as hazardous drugs if

studies in animals or humans indicate their potential to cause

cancer, developmental or reproductive toxicity, or harm to

organs”

• When it occurs at low doses

ASHP 1990; OSHA 1995, 1999

• Appendix A of NIOSH Alert

• antineoplastics; Immunosuppressive agents;Estrogens; Oxytocics; Contraceptives; 5-alphareductase inhibitors; Androgens; Antivirals;Gonadotropins; Anti-infectives; Estrogen agonist-antagonists; Skin mitotic inhibitors; Cell stimulants andproliferants

• All forms of drugs

• How do we tell if it is Hazardous?

– No Universal symbol to designate

62

Sources of Exposure

• Drug vials

• Drug preparation

• Spills

• Vapor

• Drug administration

• Patients

– Waste & laundry

• RX Waste

Workers at risk

• Shipping/receiving

• Pharmacy personnel

• Nursing personnel

• Physicians

• OR personnel

• Environmentalservices

• Laundry services

• Waste management

Exposure & Risk

Work Environment

Traditional Biological Cabinet Isolator Glove Box

Not exempt from garbing requirements

NuAir, ChemoShield

63

Storage and Compounding

• Evaluation of work environment & equipment

• Policy & Procedures

– delineation of hazardous materials

• develop list with Safety departments

– Labeling, storage, personnel issues, spillcontrol

– Education, preparation, administration,disposal

• Evaluation of workspace

– Ventilated cabinets

• Use of equipment or devices to minimizeexposure

– Needle-less

– Personal Protective Equipment

– Closed-system devices

Decontamination

• “Decontamination” of cabinets– Surface-safe (15/case) $1.43/ea

• step 1: 2% sodium hypochlorite detergent• step 2: 1% sodium thiosulfate & 0.9% benzyl alcohol• 6% Hypochloride solution

– azathioprine, bleomycin, daunorubicin, etoposide,fluorouracil, etoposide, mitomycin, vinblastine,vincristine

– cyclophosphamide, melphalan, ifosfamide, methotrexate

• “Sterilization” of cabinets– Caution Isopropyl alcohol use in Type II-A and II-B3– Must be in contact for 30 seconds

64

Administration and Cleaning

• Administration

• Skills assessed for administration

All personnel including MD’s

• Policy on tubing sets not removed from original bags

• Housekeeping and Decontamination

• All waste placed appropriate waste containers & labeled

• Routine cleaning of work environments

and rooms??

• PPE for Environmental Services??

• Blood and Urine specimens???? in the pneumatictubes?

• Linen management

• All linen bagged in yellow bags peri andpost chemo

• Linen personnel to don appropriate garb

RCRA HazardousWaste Containers

Hazardous Pharmaceutical

Waste Streams

Biohazard InfectiousWaste (Regulated Medical Waste)

Blood products, sharps, items

contaminated with liquid blood, etc.

Trace Chemo Waste Containers

RCRA empty chemotherapy vials,

syringes, IVs, tubing, gowns,

gloves, etc.

Bulk chemo in vials,

unused IV’s, P, U. toxic & ignitable D

Overtly contaminated gowns, glove,

chemo spill clean up materials

65

Education Plan

• Orientation to hazardous chemicals

- Key contacts within the organization

- Location of policies

• Encourage employees to notify their physician of theirpossible occupational exposure to hazardous drugs

• Educate employees of signs and symptoms

- Based on the agents

- Acute versus chronic

- Annual review of critical process and hazardouschemicals

- Plan in place to education on new chemicals

Staff Education Program

Medical Surveillance

– Recommendations since 1985

– NIOSH 117 document April 2007

• www.cdc.gov/niosh/docs/wp-solutions/2007-117/NIOSH

- Recommendations, NOT a mandate

– Elements of a medical surveillance program

- Reproductive and health questionnaires- at hire and periodically

- Laboratory work- Complete blood count & Urinalysis

- Physical examination at hire and thereafter forabnormal findings on health questionnaire

- Follow-up for those workers who have health changesor significant exposures

- Tracking trends with questionnaires and sick-call

66

Occupational Safety and Health Association (OSHA)

Centers for Medicare and Medicaid Services

The Joint Commission

United States Environmental Protection Agency (USEPA)

State Boards of Health (Nursing, Pharmacy, etc.)

Agencies That Could Be Involved

with Hazardous Drug Exposures

The Joint Commission VisitNovember 27 to 30, 2007

• Tracer on a Oncology patient

– Started from admission to point of administration ofNovember 28, 2007 Cyclophosphamide dose

– Visited pharmacy to observe compounding

• Use of NuAire Isolator

• Use of full garb with the Isolator

• Use of PhaSeal

• Use of Black delivery bags & RCRA waste containers

– Interviewed compounding pharmacist

• Stated ‘Nice to not have to worry about beingexposed’

• Surveyor commented in exit interview

– “Very impressive system from patient care unit to thepharmacy utilizing an isolator and the PhaSeal system”

67

NMH Process Changes

• Education of Hazards Plan

• New employee orientation & annual review

• Team meetings: pharmacy, housekeeping, nursing

• Garbing Requirements

• Shipping/receiving, housekeeping, contractors, laundry

• Segregation of regulated waste

• Defined red, yellow and black (RCRA) waste

• Signage for Hazardous Drug Use

• Signage in pharmacy where HDs are stored

• Magnets on doors of patients receiving treatment

• Medical Surveillance

• Analysis of sick-call for high risk team members

- follow-up call for all at-risk members

• Compounding personnel only, new for 2008

“Workers who are potentially exposed to chemical hazards

should be monitored in systematic program of medical

surveillance to prevent occupational injury and

disease….The purpose of surveillance is to identify the

earliest reversible biological effects so that exposure can

be reduced or eliminated before the employee sustains

irreversible damage”

OSHA Technical Manual: Controlling OccupationalExposure to Hazardous Drugs

US Department of Labor 1999

68

Question 1

A comprehensive safety program formanaging hazardous drugs shouldinclude:

A. Gap analysis of current processes tostandards

B. Education and Medical surveillance of highrisk personnel

C. Incorporation of engineering controls toprotect personnel

D. All of the above

Question 2

Medical surveillance is mandated under theOccupational Safety and HealthAssociation (OSHA)?

A. True

B. False

69

Questions…

Question 1

Were you previously informed of thestudies/research presented today?

A. Yes

B. No

70

Question 2

Will you change your approach topractice as a result of this program?

A. Yes

B. No

C. Undecided

Thank You!

Commercial Support

Provided By

Carmel Pharma, Inc.