Hazardous Medicines:Hazardous Medicines:Current Issues & Future ChallengesCurrent Issues & Future Challenges

Graham SewellGraham SewellProfessor of Clinical Pharmacy, Professor of Clinical Pharmacy,

Kingston University Kingston University

and and

Assistant Director of Pharmacy, Assistant Director of Pharmacy,

Plymouth Hospitals TrustPlymouth Hospitals Trust

NIOSH Definition of NIOSH Definition of Hazardous DrugsHazardous 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)

Presentation Outline: Focus on Presentation Outline: Focus on Antineoplastic DrugsAntineoplastic Drugs

Evidence of risk from cytotoxics: Evidence of risk from cytotoxics:

Questions…………..Questions…………..

- Risk of cytotoxic contamination in Risk of cytotoxic contamination in workplace?workplace?

- Risk of equipment/protection failure?Risk of equipment/protection failure?

- Possible health risk if exposed?Possible health risk if exposed?

MAB’s A new risk?MAB’s A new risk?

Management of risk: GuidelinesManagement of risk: Guidelines

Risk of Cytotoxic ContaminationRisk of Cytotoxic Contamination

Is there any risk?

If so, where does risk come from?

What is the evidence?

What are the implications?

Surface Contamination of Surface Contamination of Primary PackagingPrimary Packaging

Liege Study:Liege Study:

Surface of 90 vials 5-FU tested, 3 Surface of 90 vials 5-FU tested, 3 supplierssuppliers

27/90 – 5-FU above LOD (0.3ng) but 27/90 – 5-FU above LOD (0.3ng) but below LOQ (1ng)below LOQ (1ng)

3/90 – 5-FU above LOQ (4.8-18.1ng/vial)3/90 – 5-FU above LOQ (4.8-18.1ng/vial)

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

Favier et al: External Contamination of Vials

Vials of 5-FU, Etoposide, Ifosfamide, Vials of 5-FU, Etoposide, Ifosfamide, Cyclophosphamide, Doxorubicin, Docetaxel.Cyclophosphamide, Doxorubicin, Docetaxel.

100% had contamination on outer surfaces100% had contamination on outer surfaces

ContaminationContamination // vial ranged 0.5 – 2500ngvial ranged 0.5 – 2500ng

Differences between manufacturersDifferences between manufacturers

Favier et al: J Oncol Pharm Practice (2003), J Oncol Pharm Practice (2003), 99, 15-20, 15-20

Surface Contamination on Surface Contamination on Pharmacy Pre-filled SyringesPharmacy Pre-filled Syringes

Contamination: 5-FU 500mg/20ml syringeContamination: 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 = 79ugMaximum contamination = 79ug

LOD = 0.5ugLOD = 0.5ug

Preparation & AdministrationPreparation & AdministrationAreas: Surface ContaminationAreas: Surface Contamination Six US/Canadian centres studiedSix US/Canadian centres studied

Contamination detected in 75% pharmacy Contamination detected in 75% pharmacy and 65% administration areasand 65% administration areas

Pharmacy; highest levels on work surface Pharmacy; highest levels on work surface and airfoil of BSC and floor in front of BSCand airfoil of BSC and floor in front of BSC

Clinic; highest levels on floor by bedClinic; highest levels on floor by bed

Connor etal, Am J H-S Pharm (1999),56,1427Connor etal, Am J H-S Pharm (1999),56,1427

Isolators: Total Protection?Isolators: Total Protection?

Simulation in aseptic clean room, Simulation in aseptic clean room, Kingston UniversityKingston University

Experienced technicians, Experienced technicians, 25 batches over 4 days25 batches over 4 days

Sample before and after cleaningSample before and after cleaning

Validated wipe-sampling of isolator gloves, Validated wipe-sampling of isolator gloves, sleeve, base, hatch, doors, trays etc sleeve, base, hatch, doors, trays etc andand products leaving isolatorproducts leaving isolator

Preparation SchedulePreparation ScheduleDay & Session Drug Volume Syringe Size Number of Batch Day & Session Drug Volume Syringe Size Number of Batch

(ml)(ml) (ml)(ml) UnitsUnits Day 1 Session 1Day 1 Session 1 CP, 150mgCP, 150mg 7.5 7.5 1010 1010 11

CP, 500mgCP, 500mg 25 25 6060 1010 22EPI, 15mgEPI, 15mg 7.5 7.5 1010 1515 33

Day 1 Session 2Day 1 Session 2 EPI, 50mgEPI, 50mg 25 25 6060 1010 44EPI, 75mgEPI, 75mg 37.5 37.5 6060 11 55MTX, 15mgMTX, 15mg 0.6 0.6 3 3 1010 66MTX, 200mgMTX, 200mg 500 500 500ml bag500ml bag 1 1 77

Day 2 Session 1Day 2 Session 1 CP, 200mgCP, 200mg 10 10 1010 1010 88EPI, 50mgEPI, 50mg 25 25 5050 1010 1010EPI, 40mgEPI, 40mg 20 20 2020 1010 1111

Day 2 Session 2Day 2 Session 2 MTX, 20mgMTX, 20mg 0.8 0.8 3 3 1010 99MTX, 20mgMTX, 20mg 0.8 0.8 3 3 1010 1212MTX, 40mgMTX, 40mg 1.6 1.6 3 3 11 1313

Day 3 Session 1Day 3 Session 1 CP, 400mgCP, 400mg 20 20 20 20 1010 1414CP, 500mgCP, 500mg 25 25 60 60 1010 1515EPI, 20mgEPI, 20mg 10 10 10 10 1010 1616EPI, 50mgEPI, 50mg 25 25 60 60 1010 1717

Day 3 Session 2Day 3 Session 2 MTX, 100mgMTX, 100mg 500 500 500ml bag500ml bag 1 1 1818MTX, 40mgMTX, 40mg 1.6 1.6 3 3 11 1919

Day 4 Session 1Day 4 Session 1 CP, 400mgCP, 400mg 20 20 20 l20 l 1010 2020CP, 500mgCP, 500mg 25 25 60 60 1010 2121EPI, 30mgEPI, 30mg 15 15 20 20 1010 2222EPI, 40mgEPI, 40mg 20 20 20 20 1010 2323

Day 4 Session 2Day 4 Session 2 MTX, 7.5mgMTX, 7.5mg 0.7 0.7 3 3 1010 2424MTX, 40mgMTX, 40mg 1.6 1.6 3 3 11 2525

Epirubicin: Location and AmountEpirubicin: Location and Amount

Amount of EPI Recovered from Isolator Surfaces (ng/ml)Amount of EPI Recovered from Isolator Surfaces (ng/ml)

Cyclophosphamide: Location and Cyclophosphamide: Location and AmountAmount

Amount of CP Recovered from Isolator Surfaces (ng/ml)Amount of CP Recovered from Isolator Surfaces (ng/ml)

Methotrexate: Location and Methotrexate: Location and AmountAmount

Amount of MTX Recovered from Isolator Surfaces (ng/ml)Amount of MTX Recovered from Isolator Surfaces (ng/ml)

Surface Contamination of Syringes: Surface Contamination of Syringes: Number testing +veNumber testing +ve

Period 1Period 1 Period 2 Period 2BatchBatch EPI MTX CPEPI MTX CP EPI MTX CP EPI MTX CP

EPI batches:EPI batches: 44 10 10 1 1 0 0 7 7 0 0 0 0 1616 9 9 0 0 0 0 0 0 3 3 0 0 2222 10 10 1 1 0 0 10 10 1 1 4 4

MTX Batches:MTX Batches: 1212 0 0 1 1 0 0 0 0 0 0 0 0 2424 1 1 1 1 0 0 10 10 3 3 0 0

CP Batches:CP Batches: 22 0 0 0 0 0 0 0 0 0 0 0 0 88 6 6 0 0 2 2 3 3 0 0 0 0 1414 9 9 1 1 0 0 0 0 0 0 0 0

Cross-Contamination with Cross-Contamination with Biological Agents: A Real Risk?Biological Agents: A Real Risk?

““Meningitis due to iatrogenic BCG infection Meningitis due to iatrogenic BCG infection in 2 immunocompromised children”in 2 immunocompromised children”

Stone M Stone M et alet al N Engl J Med, 1995, N Engl J Med, 1995, 333333, 561, 561

Closed System for Cytotoxic Closed System for Cytotoxic HandlingHandling

Summary: Risk of ContaminationSummary: Risk of Contamination

Risk Risk isis real real

High frequency, low amountsHigh frequency, low amounts

Clear evidenceClear evidence

Contamination arises from drug vials, Contamination arises from drug vials, manipulation of drugs, isolator surfacesmanipulation of drugs, isolator surfaces

Products leaving isolators Products leaving isolators areare contaminatedcontaminated

Risk of Equipment and Protection Risk of Equipment and Protection FailureFailure

Isolators become contaminated and Isolators become contaminated and contaminate product. contaminate product. Can we clean isolators?Can we clean isolators?

Isolators leakIsolators leak

How effective is Personal Protective How effective is Personal Protective Clothing (PPE)? Clothing (PPE)? Are they likely to fail to protect?Are they likely to fail to protect?

- Gloves?Gloves?

- Gowns?Gowns?

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)

WFI 1 3 1 1 1 1

Criti-Klenz 1 1 1 1 2 2

CIP 150 1 1 1 1 3 3

CIP 100 1 1 1 1 2 2

Renu -Klenz 1 1 1 1 1 1

NpH-Klenz 1 1 1 1 1 1

Cage-Klenz 1 1 1 1 1 1

CIP 220 1 1 1 1 1 1

CIP 200CIP 200 1 1 1 1 1 1

IMSIMS 1 1 1 1 1 1

PPE : Are Gowns and Gloves PPE : Are Gowns and Gloves Effective ?Effective ?

Penetration study on 6 protective gownsPenetration study on 6 protective gowns

- 2/6 allowed penetration of 10 and 4 drug - 2/6 allowed penetration of 10 and 4 drug solutions over a 1 min test period solutions over a 1 min test period

- quality & comfort varied between gowns- quality & comfort varied between gowns

Harrison & Kloos Harrison & Kloos

J Oncol Pharm Pract (1999) 5(2), 61-66J Oncol Pharm Pract (1999) 5(2), 61-66

Permeability of GlovesPermeability of Gloves

Connor , Am J H-S Pharm. (1999),56,2450Connor , Am J H-S Pharm. (1999),56,2450

- Nitrile, latex, polyurethane and neoprene - Nitrile, latex, polyurethane and neoprene gloves tested against 18 antineoplasticsgloves tested against 18 antineoplastics

- Permeation (>1%) occurred in 4- Permeation (>1%) occurred in 4 // 864 864 in 30 minutesin 30 minutes

- Practice conditions are different to test - Practice conditions are different to test situationsituation

Possible Health Risks of Possible Health Risks of Antineoplastic DrugsAntineoplastic Drugs

Are they real ?Are they real ?

What is the evidence ?What is the evidence ?

Is the evidence too difficult to obtain ?Is the evidence too difficult to obtain ?

Carcinogenicity of Carcinogenicity of Cytotoxic DrugsCytotoxic Drugs

International Agency for Research on Cancer International Agency for Research on Cancer

11 agents and 2 combined therapies listed as 11 agents and 2 combined therapies listed as human carcinogens human carcinogens (Group 1) (Group 1)

12 agents listed as probable human 12 agents listed as probable human carcinogens carcinogens (Group 2A)(Group 2A)

11 agents listed as possible human 11 agents listed as possible human carcinogens carcinogens (Group 2B)(Group 2B)

Cytotoxics in Pregnancy : RiskCytotoxics in Pregnancy : Riskof Low Birth Wt / Birth Defectsof Low Birth Wt / Birth Defects

P. Scheepers , Nijmegen :P. Scheepers , Nijmegen :

Oncology nurses; 229 live births.Oncology nurses; 229 live births.

Reference group; 956 live births.Reference group; 956 live births.

Activity Odds RatioActivity Odds Ratio

Low Birth Wt. Cong. def.Low Birth Wt. Cong. def.

Caring/Nursing 1.8 1.4Caring/Nursing 1.8 1.4

Admin. chemo 1.4 1.8Admin. chemo 1.4 1.8

Prep. + Admin. 16.7 5.1 Prep. + Admin. 16.7 5.1

Pregnancy Category D or X Drugs in Pregnancy Category D or X Drugs in Current NIOSH AlertCurrent NIOSH Alert

USFDA

Category

No.

Agents

Definition

D 46

There is clear evidence of risk to the human fetus, but the benefits may outweigh the risk for pregnant women.

X 5

There is clear evidence that the medication causes abnormalities in the fetus. The risks outweigh any potential benefits for women who are pregnant.

Reproductive Outcomes Reproductive Outcomes (Health Care Workers)(Health Care Workers)

Endpoint No. Studies Pos/Total

No. Significant Studies

Spontaneous Abortions

4/5 2

Congenital malformations

3/4 2

Stillbirths 2/2 0(Dranitsaris et al, 2005)

Antineoplastic Drugs in Breast MilkAntineoplastic 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

American Society of Health-System American Society of Health-System Pharmacists Guidelines (2006)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.”

Oncology Nursing Society Guidelines Oncology Nursing Society Guidelines (2005)(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.”

HSE GuidelinesHSE 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.”

““New” Risk FactorsNew” Risk Factors inin Cytotoxic Handling Cytotoxic Handling

CentralisationCentralisation ofof handlinghandling (and(and risk)risk)

IncreasingIncreasing cytotoxiccytotoxic useuse

NewNew drugdrug deliverydelivery systemssystems

IncreasedIncreased outpatientoutpatient / / homehome therapytherapy

NewNew drugdrug presentations, oral dosespresentations, oral doses

Use in non-malignant diseaseUse in non-malignant disease

NewNew agents – Targeted therapiesagents – Targeted therapies

TrastuzumabTrastuzumab

Monoclonal antibodies: Risk Monoclonal antibodies: Risk issuesissues

Allergic and immunogenic reactionsAllergic and immunogenic reactions

““Cytokine storm” E.g. TGN1412Cytokine storm” E.g. TGN1412

Cross-reaction with important proteinsCross-reaction with important proteins

Complement-mediated cytotoxicityComplement-mediated cytotoxicity

Handling risk linked to NPSA 20 riskHandling risk linked to NPSA 20 risk

Langford etal Langford etal Hospital Pharmacist (2008) 15, 60-63Hospital Pharmacist (2008) 15, 60-63

Debate: Debate: Hospital Pharmacist (2008) 15, 138-139Hospital Pharmacist (2008) 15, 138-139

Conclusions Conclusions Evidence of risk of Evidence of risk of a) contamination and a) contamination and b) adverse health effects .b) adverse health effects .

Risks with new & biological agents requires Risks with new & biological agents requires greater understanding and research.greater understanding and research.Use simple, practical methods of control.Use simple, practical methods of control.Evaluate new technologies Evaluate new technologies e.g. Closed systemse.g. Closed systems

Recognise limitations of equipment and Recognise limitations of equipment and procedures procedures (e.g. cleaning)(e.g. cleaning)

Implement simple risk management and Implement simple risk management and validatevalidate

Key Information SourcesKey Information Sources

International Society of Oncology International Society of Oncology Pharmacy Practitioners Standards. Pharmacy Practitioners Standards. www.isopp.org

NIOSH Alert NIOSH Alert www.cdc.gov/niosh

MARCH Guidelines MARCH Guidelines www.marchguidelines.com

Contact:Contact: G.J.Sewell@kingston.ac.uG.J.Sewell@kingston.ac.ukk