Hazardous Medicines: Current Issues

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Hazardous MedicinesCurrent Issues Future
Challenges

• Graham Sewell
• Professor of Clinical Pharmacy,
• Kingston University
• and
• Assistant Director of Pharmacy,
• Plymouth Hospitals Trust

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NIOSH Definition of Hazardous 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)

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Presentation Outline Focus on Antineoplastic
Drugs

• Evidence of risk from cytotoxics
  Questions..
• Risk of cytotoxic contamination in workplace?
• Risk of equipment/protection failure?
• Possible health risk if exposed?
• MABs A new risk?
• Management of risk Guidelines

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Risk of Cytotoxic Contamination

• Is there any risk?
• If so, where does risk come from?
• What is the evidence?
• What are the implications?

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Surface Contamination of Primary Packaging

• Liege Study
• Surface of 90 vials 5-FU tested, 3 suppliers
• 27/90 5-FU above LOD (0.3ng) but below LOQ
  (1ng)
• 3/90 5-FU above LOQ (4.8-18.1ng/vial)
• Delporte etal EHP (1999) 5 (3) 119-121

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Favier et al External Contamination of Vials

• Vials of 5-FU, Etoposide, Ifosfamide,
  Cyclophosphamide, Doxorubicin, Docetaxel.
• 100 had contamination on outer surfaces
• Contamination / vial ranged 0.5 2500ng
• Differences between manufacturers
• Favier et al J Oncol Pharm Practice (2003), 9,
  15-20

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Surface Contamination on Pharmacy Pre-filled
Syringes

• Contamination 5-FU 500mg/20ml syringe
• - 8/35 syringes (23) contaminated
• - 3/15 blind-hubs (20) contaminated
• Maximum contamination 79ug
• LOD 0.5ug

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Preparation AdministrationAreas Surface
Contamination

• Six US/Canadian centres studied
• Contamination detected in 75 pharmacy and 65
  administration areas
• Pharmacy highest levels on work surface and
  airfoil of BSC and floor in front of BSC
• Clinic highest levels on floor by bed
• Connor etal, Am J H-S Pharm (1999),56,1427

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Isolators Total Protection?

• Simulation in aseptic clean room, Kingston
  University
• Experienced technicians, 25 batches over 4
  days
• Sample before and after cleaning
• Validated wipe-sampling of isolator gloves,
  sleeve, base, hatch, doors, trays etc and
  products leaving isolator

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Preparation Schedule

• Day Session Drug Volume Syringe
  Size Number of Batch
• (ml) (ml) Units
• Day 1 Session 1 CP, 150mg 7.5 10 10 1
• CP, 500mg 25 60 10 2
• EPI, 15mg 7.5 10 15 3
• Day 1 Session 2 EPI, 50mg 25 60 10 4
• EPI, 75mg 37.5 60 1 5
• MTX, 15mg 0.6 3 10 6
• MTX, 200mg 500 500ml bag
  1 7
• Day 2 Session 1 CP, 200mg 10 10 10 8
• EPI, 50mg 25 50 10 10
• EPI, 40mg 20 20 10 11
• Day 2 Session 2 MTX, 20mg 0.8 3 10 9
• MTX, 20mg 0.8 3 10 12
• MTX, 40mg 1.6 3 1 13
• Day 3 Session 1 CP, 400mg 20 20 10 14
• CP, 500mg 25 60 10 15
• EPI, 20mg 10 10 10 16
• EPI, 50mg 25 60 10 17

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Epirubicin Location and Amount

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

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Cyclophosphamide Location and Amount

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

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Methotrexate Location and Amount

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

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Surface Contamination of Syringes Number testing
ve

• Period 1 Period 2
• Batch EPI MTX CP
  EPI MTX CP
• EPI batches
• 4 10 1 0 7 0 0
• 16 9 0 0 0 3 0
• 22 10 1 0 10 1 4
• MTX Batches
• 12 0 1 0 0 0 0
• 24 1 1 0 10 3 0
• CP Batches
• 2 0 0 0 0 0 0
• 8 6 0 2 3 0 0
• 14 9 1 0 0 0 0

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Cross-Contamination with Biological Agents A
Real Risk?

• Meningitis due to iatrogenic BCG infection in 2
  immunocompromised children
• Stone M et al N Engl J Med, 1995, 333, 561

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Closed System for Cytotoxic Handling
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Summary Risk of Contamination

• Risk is real
• High frequency, low amounts
• Clear evidence
• Contamination arises from drug vials,
  manipulation of drugs, isolator surfaces
• Products leaving isolators are contaminated

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Risk of Equipment and Protection Failure

• Isolators become contaminated and contaminate
  product. Can we clean isolators?
• Isolators leak
• How effective is Personal Protective Clothing
  (PPE)? Are they likely to fail to protect?
• Gloves?
• Gowns?

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Cleaning Effectiveness No. Wipes to Remove Drug
(ltLOD)
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 200 1 1 1 1 1 1
IMS 1 1 1 1 1 1
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PPE Are Gowns and Gloves Effective ?

• Penetration study on 6 protective gowns
• - 2/6 allowed penetration of 10 and 4 drug
  solutions over a 1 min test period
• - quality comfort varied between gowns
• Harrison Kloos
• J Oncol Pharm Pract (1999) 5(2), 61-66

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Permeability of Gloves

• Connor , Am J H-S Pharm. (1999),56,2450
• - Nitrile, latex, polyurethane and neoprene
  gloves tested against 18 antineoplastics
• - Permeation (gt1) occurred in 4 / 864 in
  30 minutes
• - Practice conditions are different to test
  situation

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Possible Health Risks of Antineoplastic Drugs

• Are they real ?
• What is the evidence ?
• Is the evidence too difficult to obtain ?

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Carcinogenicity of Cytotoxic Drugs

• International Agency for Research on Cancer
• 11 agents and 2 combined therapies listed as
  human carcinogens (Group 1)
• 12 agents listed as probable human
  carcinogens (Group 2A)
• 11 agents listed as possible human
  carcinogens (Group 2B)

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Cytotoxics in Pregnancy Riskof Low Birth Wt /
Birth Defects

• P. Scheepers , Nijmegen
• Oncology nurses 229 live births.
• Reference group 956 live births.
• Activity Odds Ratio
• Low Birth Wt.
  Cong. def.
• Caring/Nursing 1.8
  1.4
• Admin. chemo 1.4
  1.8
• Prep. Admin. 16.7
  5.1

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Pregnancy Category D or X Drugs in Current 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.
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Reproductive Outcomes (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) (Dranitsaris et al, 2005) (Dranitsaris et al, 2005)
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Antineoplastic 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

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American Society of Health-System 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.

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Oncology Nursing Society Guidelines (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.

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HSE 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 womans
  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 childs health.

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New Risk Factors in Cytotoxic
Handling

• Centralisation of handling (and risk)
• Increasing cytotoxic use
• New drug delivery systems
• Increased outpatient / home therapy
• New drug presentations, oral doses
• Use in non-malignant disease
• New agents Targeted therapies

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Trastuzumab
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Monoclonal antibodies Risk issues

• Allergic and immunogenic reactions
• Cytokine storm E.g. TGN1412
• Cross-reaction with important proteins
• Complement-mediated cytotoxicity
• Handling risk linked to NPSA 20 risk
• Langford etal Hospital Pharmacist (2008) 15,
  60-63
• Debate Hospital Pharmacist (2008) 15, 138-139

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Conclusions

• Evidence of risk of
• a) contamination and
• b) adverse health effects .
• Risks with new biological agents requires
  greater understanding and research.
• Use simple, practical methods of control.
• Evaluate new technologies e.g. Closed systems
• Recognise limitations of equipment and procedures
  (e.g. cleaning)
• Implement simple risk management and validate

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Key Information Sources

• International Society of Oncology Pharmacy
  Practitioners Standards. www.isopp.org
• NIOSH Alert
  www.cdc.gov/niosh
• MARCH Guidelines www.marchguidelines.com
• Contact G.J.Sewell_at_kingston.ac.uk