Hazardous Medicines:
Current Issues & Future Challenges
Graham Sewell
Professor of Clinical Pharmacy,
Kingston University
and
Assistant Director of Pharmacy,
Plymouth Hospitals Trust
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)
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?
MAB’s A new risk?
Management of risk: Guidelines
Risk 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
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
Favier etal: 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
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
Preparation & Administration
Areas: 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
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
Preparation Schedule
Day & Session
Day 1 Session 1
Day 1 Session 2
Day 2 Session 1
Day 2 Session 2
Day 3 Session 1
Day 3 Session 2
Day 4 Session 1
Day 4 Session 2
Drug
Volume
CP, 150mg
CP, 500mg
EPI, 15mg
EPI, 50mg
EPI, 75mg
MTX, 15mg
MTX, 200mg
CP, 200mg
EPI, 50mg
EPI, 40mg
MTX, 20mg
MTX, 20mg
MTX, 40mg
CP, 400mg
CP, 500mg
EPI, 20mg
EPI, 50mg
MTX, 100mg
MTX, 40mg
CP, 400mg
CP, 500mg
EPI, 30mg
EPI, 40mg
MTX, 7.5mg
MTX, 40mg
Syringe Size
(ml)
(ml)
7.5
25
7.5
25
37.5
0.6
500
10
25
20
0.8
0.8
1.6
20
25
10
25
500
1.6
20
25
15
20
0.7
1.6
10
60
10
60
60
3
500ml bag
10
50
20
3
3
3
20
60
10
60
500ml bag
3
20 l
60
20
20
3
3
Number of
Batch
Units
10
10
15
10
1
10
1
10
10
10
10
10
1
10
10
10
10
1
1
10
10
10
10
10
1
1
2
3
4
5
6
7
8
10
11
9
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Epirubicin: Location and Amount
Amount of EPI Recovered from Isolator Surfaces (ng/ml)
Cyclophosphamide: Location and
Amount
Amount of CP Recovered from Isolator Surfaces (ng/ml)
Methotrexate: Location and
Amount
Amount of MTX Recovered from Isolator Surfaces (ng/ml)
Surface Contamination of Syringes:
Number testing +ve
Batch
Period 1
EPI
MTX
CP
Period 2
EPI
MTX
CP
EPI batches:
4
16
22
10
9
10
1
0
1
0
0
0
7
0
10
0
3
1
0
0
4
MTX Batches:
12
24
0
1
1
1
0
0
0
10
0
3
0
0
CP Batches:
2
8
14
0
6
9
0
0
1
0
2
0
0
3
0
0
0
0
0
0
0
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
Closed System for Cytotoxic
Handling
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
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?
Cleaning Effectiveness: No. Wipes to Remove
Drug (<LOD)
5-FU
(WFI)
5-FU
(N/S)
CP
(WFI)
CP
(N/S)
DOX
(WFI)
DOX
(N/S)
WFI
Criti-Klenz
CIP 150
1
1
1
3
1
1
1
1
1
1
1
1
1
2
3
1
2
3
CIP 100
Renu -Klenz
NpH-Klenz
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
2
1
1
Cage-Klenz
CIP 220
CIP 200
IMS
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Test
Detergent
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
Permeability of Gloves
Connor , Am J H-S Pharm. (1999),56,2450
- Nitrile, latex, polyurethane and neoprene
gloves tested against 18 antineoplastics
- Permeation (>1%) occurred in 4 / 864
in 30 minutes
- Practice conditions are different to test
situation
Possible Health Risks of
Antineoplastic Drugs
Are they real ?
What is the evidence ?
Is the evidence too difficult to obtain ?
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)
Cytotoxics in Pregnancy : Risk
of 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
Pregnancy Category D or X Drugs in
Current NIOSH Alert
USFDA No.
Category Agents
D
46
X
5
Definition
There is clear evidence of risk to the
human fetus, but the benefits may
outweigh the risk for pregnant
women.
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
(Health Care Workers)
Endpoint
Spontaneous
Abortions
Congenital
malformations
Stillbirths
(Dranitsaris et al, 2005)
No. Studies
Pos/Total
No. Significant
Studies
4/5
2
3/4
2
2/2
0
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
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.”
Oncology Nursing Society Guidelines
(2005)
“Allow employees who are pregnant,
actively trying to conceive, or breastfeeding 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 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 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
Trastuzumab
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
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
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@kingston.ac.uk