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Specialized services CHAPTER 40
conventional (cytotoxic) chemotherapy. Other examples of targeted therapies include bevacizumab and
rituximab which are used for the treatment of colorectal cancer and certain lymphomas, respectively.
Although the targeted therapies are more specific
than conventional chemotherapy agents, toxicity is
still a major issue, with the risk of side-effects from
conventional agents (e.g. cardiotoxicity caused by
doxorubicin) being augmented by the targeted therapy. The targeted therapies are not considered to be
cytotoxic agents, although there is some evidence that
these drugs can cause indirect cytotoxic effects.
Dosage forms used in
chemotherapy
The majority of chemotherapy doses are administered
as injections or infusions. The parenteral route offers
the advantages of assured bioavailability, careful control over the rate of drug administration and the sequence of administration for regimens based on two
or more drugs, and also the ability to stop drug administration immediately in the event of severe, acute
adverse effects. However, the parenteral route is invasive, uncomfortable and inconvenient for the patient, and may be associated with complications
such as infection, extravasation and thromboembolism. The majority of chemotherapy injections or
infusions are given in the hospital setting, usually at
specialized outpatient clinics, where nursing and
medical support is readily available.
Parenteral cytotoxics are available as sealed vials
containing freeze-dried powders or sterile, concentrated solutions. These presentations are designed to
provide an adequate shelf life (usually >2 years) for
the manufacturer and the user. The freeze-dried
powders require reconstitution with an appropriate
diluent. The reconstituted solution or the infusion
concentrate may then require further dilution before
being filled into syringes, infusion bags or infusion
devices for administration to patients. The process
of taking chemotherapy doses, as provided by the
manufacturer, and preparing the required dose in a
ready to use form for administration to the patient is
often simply termed ‘reconstitution’, although in
practice, it is much more than that.
Parenteral cytotoxics can be administered via the
following routes:
*
By a syringe as a bolus or slow-bolus injection,
usually into a cannula
*
By slow bolus injection into the side arm of an
infusion
*
By addition of a cytotoxic agent directly into an
infusion fluid which is then administered over a
predetermined infusion period.
Syringe drivers and ambulatory infusion devices can
be filled with cytotoxic medicines for use in the community by patients receiving home chemotherapy.
Care must be taken when checking prescriptions
and administering chemotherapy that the route of
administration has not been transposed. The vinca
alkaloids (e.g. vincristine), for example, must never
be injected by the intrathecal route, and when this has
occurred as a result of an error, the results have always
been fatal.
The focus of this chapter is mainly on the provision
of parenteral cytotoxic medication for hospital and
home patients. However, it should be noted that cytotoxic medicines are available in a range of oral dosage forms including tablets, capsules and suspensions.
Recent advances in drug development have overcome
some of the bioavailability issues associated with oral
chemotherapy and have provided very effective treatments by the oral route. Capecitabine, for example, is
a pro-drug of 5-fluorouracil which is selectively activated in the liver and in tumour tissue. A discussion of
oral chemotherapy is beyond the scope of this text,
and the reader is referred to the British Oncology
Pharmacy Association’s ‘Position statement on care
of patients receiving oral anticancer drugs’ and the
Society of Hospital Pharmacists of Australia’s ‘Standards of practice for the provision of oral chemotherapy for the treatment of cancer’ for more information
on this increasingly important area (see Appendix 5).
Dose and schedule of chemotherapy
An explanation is given in Chapter 26 of how to calculate doses on the basis ofthe patient’s body surfacearea
(BSA). The use of BSA is designed to reduce interpatient variability in responding to chemotherapy, although the scientific validity of this approach is now
being challenged. In the case of carboplatin, the dose is
calculatedaccordingto thepatient’s renal functionand
a pre-defined pharmacokinetic parameter (area under
the plasma concentration–time curve or AUC).
Clinical pharmacists specialized in oncology and
haematologyare routinely expected to validatechemotherapy protocols and prescribing systems, as well as
449
SECTION FOUR Dispensing and related pharmaceutical practice activities
calculating the doses required. In some parts of the
UK, appropriatelyqualifiedpharmacistsprescribechemotherapy as supplementary prescribers (see Ch. 17).
Cytotoxic agents can be used individually or in
combination. Many oncology centres use a combination of medicines in nationally recognized, evidencebased protocols. These are usually denoted by the
initial letters of each medicine used in the regimen,
e.g. FEC which stands for 5-fluorouracil, epirubicin
and cyclophosphamide in combination. Combinations of cytotoxic agents can increase toxicity, but
providing they have a differing spectrum of toxicity,
drug combinations may enable the administration of a
higher dose-intensity. The risk of emergence of resistant tumour cells is also (at least theoretically) reduced. Further information about chemotherapy
regimens can be found in the malignant disorders
chapter of Clinical Pharmacy and Therapeutics
(Walker & Whittlesea 2007).
Occupational exposure risks
For many years there have been concerns regarding
the handling of cytotoxic agents by healthcare workers who are involved in the preparation and administration of these medicines. Cytotoxic drug exposure
has been associated with various acute toxicities
including headache, rash, nausea and dizziness. However, the more serious risks of occupational exposure
are related to the potential mutagenic, carcinogenic
and teratogenic effects of cytotoxic drugs. The International Agency for Research on Cancer (IARC) classifies 11 cytotoxic drugs and two drug combinations
as known human carcinogens, 12 drugs as probable
human carcinogens and a further 11 drugs as possible
human carcinogens. The United States National Institute of Occupational Health and Safety (NIOSH)
issued an alert in 2004 which identified 51 drugs as
potential risks to human reproduction. Routes of
cytotoxic exposure include ingestion, inhalation, inadvertent inoculation (needle-stick injury) and skin
contact. The latter is thought to be the most significant risk for occupational exposure.
The severity of these potential health risks requires
that cytotoxic drugs are handled and used in controlled, contained environments by staff provided
with adequate training and personal protective equipment (e.g. gloves, gowns, eye protection). To control
these risks, and also to reduce the risk of medication
errors, cytotoxic agents are prepared under strict
aseptic conditions in designated areas within a hospi-
tal pharmacy (centralized service) or in dedicated
pharmacy aseptic units attached to chemotherapy
clinics. In the UK, this requirement is set out and
enforced by the Health and Safety Executive.
Pharmacy staff preparing cytotoxic agents must be
fully trained in the necessary aseptic and safe handling
techniques and must be fully aware of the potential
health risks and the precautions that are required
when handling cytotoxic drugs. Nursing staff must
also be taught strict handling and administration techniques to ensure that they do not expose themselves
or patients and carers to any unnecessary risks. At one
time, it was thought necessary for annual health
checks and full blood counts to be carried out on all
staff involved in the preparation and administration of
cytotoxic drugs. Current opinion suggests that such
checks are of little value, and that resources should
instead be invested in the development and validation
of safe procedures, staff training, competency assessment, containment facilities (isolators) and protective
equipment. Procedures also need to be put in place
for emergency situations, such as a cytotoxic spillage.
Published guidelines include the following areas of
safe practice:
*
Personnel handling cytotoxics, including training
and competency
*
Facilities and containment systems used for
preparation
*
Techniques and precautions
*
Dealing with spillage
*
Disposal of cytotoxic drugs and cytotoxic waste
*
Labelling, packaging and distribution
*
Administration of cytotoxics drugs.
Useful guidelines on cytotoxic handling include The
Cytotoxics Handbook (Allwood et al 2002), The
Management and Awareness of Risks of Cytotoxic
Handling (MARCH) at www.marchguidelines.com
and the International Society of Oncology Pharmacy
Practitioners (ISOPP) guidelines on safe handling at
www.isopp.org.
Provision of a pharmacy-based chemotherapy preparation service
The provision of chemotherapy preparation (reconstitution) services requires that aseptic manipulation of
pharmaceuticals is combined with protection of the
operator and environment from cytotoxic exposure.
450
Specialized services CHAPTER 40
Simultaneous protection of both the pharmaceutical
product and the staff involved in its preparation is
technically demanding and requires carefully developed systems and procedures together with extensive
validation. The principles of the guidelines on cytotoxic handling (above) must be integrated with the
principles of good pharmaceutical manufacturing
practice. The establishment of a chemotherapy preparation service is not a trivial undertaking and a detailed business case defining the scope and need for
the service is fundamental to achieve the support of
hospital managers. This should include costings for
facilities and equipment, maintenance costs, staff,
consumables and drugs costs, together with funding
for training and validation of staff. An outline capacity
plan should ensure that the service is capable of meeting current and future demand; for example, the service should be able to meet the rising demand for
targeted therapies.
The management of chemotherapy preparation services presents numerous challenges; balancing the requirement for stringent safety and quality assurance
with the need to provide a timely and responsive service. The demand for chemotherapy, and hence the
workload, can fluctuate dramatically. This adds to
the difficulty in providing a service that is costeffective, although new initiatives such asdose-banding
(see later in the chapter) have helped in this respect.
Despite the challenges outlined above, it is important that pharmacy staff ‘own’ chemotherapy preparation services and take a clear lead. In the UK
National Patient Safety Agency (NPSA) Alert 20 on
injectable medicines, it is clear that application of the
risk assessment guidelines places all cytotoxic drugs,
and most chemotherapy drugs, in the high-risk category. It is therefore essential that these medicines are
prepared by specialized hospital pharmacy aseptic
units or, alternatively, by appropriate commercial
compounding providers. Pharmacy staff offer a
unique combination of skills and expertise, including
the practice of aseptic technique, a wide clinical
knowledge of cancer chemotherapy, familiarity with
formulation and drug stability issues, the application
of good manufacturing practice (GMP), quality assurance (QA) and quality control (QC) to aseptic preparation and considerable experience in working with
standard operating procedures (SOPs), batch documentation and checking procedures. These are key
attributes that help to ensure the provision of safe,
effective chemotherapy and contribute towards minimizing the risks of occupational exposure to drugs
used in the treatment of cancer.
Training required for staff
preparing cytotoxics
All personnel involved in preparing and handling of
cytotoxics require training and competency assessment in the appropriate techniques. This should include training for pharmacists, pre-registration
graduates and all technical staff and pharmacy assistants working in this field. On a practical level, all staff
must be aware of the following over and above standard aseptic technique and the application of GMP to
aseptic preparation:
*
Procedures required on receipt of a prescription for
chemotherapy (electronic or paper), including
prescription checking or ‘screening’
*
Completion of worksheets or batch documents,
and assembly of the required materials for
chemotherapy preparation
*
Changing procedures required prior to working
in a clean room environment
*
General operation of containment workstations
(Class II safety cabinets and isolators) and
techniques for the safe handling and manipulation
of cytotoxic drugs
*
Cleaning and disposal procedures prior to and
following aseptic procedures
*
Safe storage and transportation of chemotherapy
*
Background information on commonly used
chemotherapy drugs and protocols
*
Local policies and procedures for the operation of
pharmacy aseptic services, relevant health and
safety legislation and national and/or international
guidelines on cytotoxic handling.
Validation of operator
techniques
Prior to commencing work on reconstitution of cytotoxics, an operator’s competence in this field must be
assessed. This is achieved by validating operator techniques. The operator is asked to carry out broth transfer simulations where solutions of sterile broth are
transferred from one vial or container to another.
The aim of the simulation is to replicate the aseptic
transfer techniques which would routinely be used
when preparing sterile cytotoxic products. All work
is carried out under strictly controlled aseptic conditions. The broth-filled vials can then be incubated for
an appropriate time (7–14 days) and examined for
451
SECTION FOUR Dispensing and related pharmaceutical practice activities
microbiological growth. This procedure can be used in
conjunction with observing the operator at work to
determine operator competence in aseptic transfer
techniques (see also Ch. 29).
Each operator undergoing training is required to
undertake a predetermined number of broth transfer
simulations. Operators must achieve negative results
(no growth after incubation) on each occasion before
they are deemed capable of preparing cytotoxic
agents. The number of broth simulations undertaken
can vary from one hospital to another but typically
each operator and each process would be re-validated
at least every 3 months. Training procedures should be
reviewed on a regular basis and retraining and refresher courses made available to all staff. Operators routinely incorporate environmental monitoring tests
such as settle plates and finger-dab plates into the
production schedule as part of the QA process. A
member of staff with environmental monitoring
results outside of predefined action levels should be
retrained and revalidated before resuming aseptic
preparation work. Expert guidance on the validation
and monitoring of aseptic compounding has been
published in The Quality Assurance of Aseptic
Services by the NHS Quality Control Committee
(Beaney 2006).
Certain handling problems can be encountered
when dealing with cytotoxic agents. The formation
of an aerosol on removing a needle from a vial containing a cytotoxic agent can result from pressure differences between the inside of the vial and the syringe.
This is known as ‘aerosolization’ and can be prevented
by inserting a venting needle into the vial or using a
specialized reconstitution device to allow air pressures to equilibrate during addition or withdrawal of
solutions. Operator technique in the safe handling of
cytotoxic drugs can be assessed by simulating aseptic
transfer processes using a sterile solution containing a
fluorescent dye such as quinine hydrochloride. Any
splashes or spillage on the work area or equipment,
indicative of poor technique, can be visualized using a
portable ultraviolet (UV) lamp. Further details on this
type of operator competency assessment can be found
in The Cytotoxics Handbook (Allwood et al 2002). As
with assessment of aseptic technique, safe handling
should be evaluated using a combination of simulation
and expert observation.
Documentation required for
cytotoxics
On receipt of a prescription for a cytotoxic agent
a number of procedures must be undertaken.
Figure 40.1 shows the areas of work in which a phar-
macist may have involvement.
When the prescription is received, it is checked by
an experienced oncology pharmacist to ensure the
accuracy of patient details and dosage calculations
and that the presentation or dose form is suitable.
The prescription must be validated against an approved chemotherapy protocol, where the drugs,
doses, dose intervals and routes of administration
are clearly defined. Many chemotherapy regimens
are administered in ‘cycles’, with 2–3 week intervals
between them. It is essential that patients receive the
correct number of cycles of treatment at the correct
intervals. Drug monographs and the manufacturer’s
Summary of Product Characteristics can be consulted
to check drug-specific details including, for example,
shelf life of the reconstituted product and the recommended diluents.
Figure 40.1*Documentation required for cytotoxic services. (From Allwood et al 1997, reproduced with permission.)
452
Specialized services CHAPTER 40
Information from the prescription is transferred to
a worksheet or batch document and details of medicine(s) required, diluent and volume for reconstitution are recorded together with the number of drug
vials required. Details of batch numbers and expiry
date for each component used, all dose and dilution
calculations, preparation methods, container(s) to be
used, time and date of preparation, and expiry of
the final product are also required. Additionally, a
sample label is attached to the worksheet. Most chemotherapy preparation units use preprinted worksheets for each chemotherapy protocol, with a
pharmacist-approved master document from which
copies are made. Alternatively, some units use a
computer-based system which contains a database
of all approved chemotherapy protocols. Examples
of such systems in the UK include Oncology Patient
Management Audit System (OPMAS) and Chemocare. These systems produce batch documents and
labels, and although computer-generated documents
are probably less prone to error, it is essential that all
computer systems are fully validated before use.
Labels for cytotoxic medicines are conventionally
printed on a yellow background and include the term
‘cytotoxic’, although many units prefer black print on
a white background for clarity. Labels should include
the following information:
*
Patient’s name, hospital number and ward or clinic
name
*
Drug name, total quantity and final volume of
infusion
*
Vehicle in which the drug is prepared (e.g. 0.9%
sodium chloride)
*
Batch number, expiry date and storage conditions
required
*
Hospital pharmacy name and address
*
Route of administration and infusion rate.
When the worksheet is complete, the materials required for the reconstitution procedure are collected
together in a marshalling area (adjacent to the clean
room) and placed in a suitable plastic tray. The documents and components selected are then subjected to
an initial check before transfer to the designated clean
room. After preparation has been completed, the finished product(s) and used or part-used vials are
returned in the tray, together with batch documents,
for labelling, inspection and release. Some cytotoxic
agents require protection from light and are sealed in
opaque plastic overwraps which will also require labelling. The pharmacist responsible for the release of
the prepared medicines will check all details on the
worksheets and will reconcile the number of drug
vials used in the preparation. If all of these details
are in order, the pharmacist will sign the worksheet
or batch documents to signify approval, and the medicines are delivered to the clinic, ward or patient, as
appropriate. All batch documents must be retained,
and many hospitals in the UK are expected to hold
these for up to 13 years after the date of preparation.
Cytotoxic preparation areas
In the UK, and in many parts of Europe, pharmaceutical isolators are used for cytotoxic preparation. In
addition to providing aseptic conditions for preparation of the product, isolators are designed to protect
the operator and the clean room environment from
cytotoxic contamination. To achieve this, many isolators operate under negative pressure with respect to
the clean room, and the exhaust air is externally
ducted via a high-efficiency particulate air (HEPA)
filter. All isolators should be located in a classified
clean room, although the grade of the clean room
environment required is dependent upon the isolator
transfer system.
It is generally accepted that isolators offer greater
operator protection than open-fronted Class II safety
cabinets, although there is little published evidence to
support this view. The main disadvantages of isolators
include limited access for equipment and difficulties
in cleaning and removing cytotoxic residues. Gas sterilizable isolators enable sterilization of the outer surface of vials and components used in the preparation
process. Gases such as vapourized hydrogen peroxide
are pumped into the isolator to sterilize the inside of
the isolator and the outer surface of components in
situ, prior to manipulation. This increases assurance
that the aseptic environment is maintained, but the
validation of gas-sterilization cycles can be complex.
For a more detailed discussion of aseptic preparation facilities, the reader is referred to Chapter 29.
Techniques and precautions
When handling cytotoxics, it is vital that the appropriate protective clothing is worn. Operators using
clean room facilities must wear appropriate clean
room clothing, with the addition of chemotherapy
gowns or armlets for extra protection. These garments
are non-shedding and have an absorbent surface and
impermeable backing. This design reduces the risk of
splashing of solutions on contact with the gown, and
453
SECTION FOUR Dispensing and related pharmaceutical practice activities
also protects the operator from skin contact by cytotoxic drugs. Normally full clean room suits are worn
beneath the chemotherapy gown so it is important to
ensure that the clean room temperature is carefully
controlled. Gloves designed specifically for cytotoxic
handling are available and these are normally fabricated from a nitrile material. Gloves should also be worn
for handling cytotoxic drug vials outside the clean
rooms as these can be contaminated with cytotoxic
residues on the outer surface. For operators working
in an isolator workstation, the use of a face mask is
considered optional from the operator protection
viewpoint, but, in accordance with good aseptic practice, face masks should always be used to cover facial
hair.
Product segregation is crucial in all aseptic work to
avoid any risk of product mix up. In the case of cytotoxic chemotherapy, any such error could be lethal to
the patient. For this reason, only one product, or one
batch of product, is permitted within the isolator or
Class II workstation at any one time.
Reconstitution procedures
When carrying out reconstitution procedures, certain
precautions must be taken:
*
Vials and outer packs of consumables should be
sprayed with sterile 70% alcohol and wiped with a
sterile swab before being introduced into the clean
room and the process repeated before introducing
these materials into the isolator or Class II cabinet
workstation. Rubber stoppers on vials should be
swabbed with a sterile swab prior to removal of
liquid.
*
Transfer of liquids to and from vials requires the
insertion of a venting needle with hydrophobic
filter into the vial or the use of a vented
reconstitution device. These devices, which are
described below, ensure pressure equalization and
reduce the risk of aerosol generation.
*
Luer lock syringes with wide-bore needles should
be used for all procedures to allow free flow in the
fluid pathway and to avoid the risk of syringes and
needles becoming disconnected during fluid
transfer.
*
To ensure that no further additions are made to
cytotoxic infusions outside the pharmacy
preparation area, all completed products in syringe
form should be sealed with a blind hub before
removal from the cytotoxic cabinet (Fig. 40.2).
An additive plug or cap must be placed on each
minibag once additions are complete.
Figure 40.2*(A) Syringe with deadender or blind hub in posi-
tion. (B) Minibag with additive plug.
The vials that contain cytotoxic agents are effectively
a closed system which contains either a powder requiring reconstitution or a drug concentrate requiring
withdrawal from the vial into a syringe. In each case,
equalization of pressure within the vial is required to
allow withdrawal from it. This can readily be achieved
by inserting a sterile 0.2 mm hydrophobic filter venting needle into the vial to facilitate liquid transfer.
Ordinary needles with no hydrophobic filter must
454
Specialized services CHAPTER 40
not be used for venting due to the risk of leakage of
cytotoxic solution from the needle. Alternatively, reconstitution devices are available to help with the
reconstitution process. Some of these devices consist
of a small plastic spike with an integral hydrophobic
filter. These devices are useful for rapid transfer of
solutions, but the large needle bore can produce large
holes in the rubber bung of cytotoxic vials, thus increasing the risk of leakage. The CytoSafe needle is a
commonly used example of this type of product. This
device consists of a needle which is vented to allow
equilibrium of pressure between the vial and the syringe. It is useful for reconstitution of large vials or
when more than one vial is required for a dose
(Fig. 40.3). However, care must be taken when withdrawing or adding liquid to a vial as the filter may
become blocked.
More recently, advanced ‘closed systems’ using
needle-free technologies have been designed for cytotoxic handling. These devices virtually eliminate the
risks of cytotoxic aerosol formation and operator
needle-stick injuries. An example of this type of device is the Tevadaptor (Fig. 40.4). The Tevadaptor
system comprises a vial adaptor to access the drug
Figure 40.3*(A) CytoSafe needle and (B) reconstitution set-
up. (Courtesy of Baxa Corporation.)
vial, and a syringe adaptor which fits securely onto a
luer lock syringe and enables needle-free docking with
the vial adaptor. These components allow the closedsystem, needle-free addition of diluents to the drug
vial for cytotoxic reconstitution, and also the withdrawal of liquids from drug vials into syringes. The
spike port adaptor and the connecting set enable a
syringe adaptor to dock with an intravenous (IV)
bag for addition of additives to the infusion. The
two sets provide for connection to the giving set by
either a spike (spike port adaptor) or via a luer fitting
(connecting set). Alternatively, the luer lock adaptor
can be used to access infusion bags fitted with luer
additive ports using the syringe adaptor.
The Tevadaptor and other closed reconstitution
systems have been shown in studies to be effective
in reducing cytotoxic contamination in the work area,
and also on products leaving the isolator. The use of
these devices will, inevitably, increase costs of the
compounding process.
Cleaning the work area
Cytotoxic workstations, particularly isolators, can be
difficult to clean. This can result in a build-up of
cytotoxic contamination within the isolator with the
potential to increase the risk of contamination of both
the operator and the outer surfaces of preparations
leaving the isolator. The amount of contamination in
isolators can be reduced by good technique and by
conducting the aseptic manipulation work on a chemotherapy preparation mat. These are sterile mats
with an absorbent surface and an impermeable backing which will cover a large proportion of the isolator
or Class II cabinet work surface. Any minor spillage is
contained on the mat, which is disposable and normally replaced after each day or each work session.
When cleaning isolators or Class II workstations,
it is important to recognize that most cytotoxic
drugs are water soluble. For this reason, either sterile
water or a sterile aqueous-based detergent solution
should be used as the first cleaning agent, together
with sterile absorbent wipes. This clean should
then be followed with a spray and wipe of 70% alcohol
to sanitize the surfaces and maintain the aseptic
environment.
Effective cleaning is also essential to reduce the risk
of cross-contamination of drugs being prepared in the
isolator. There is documented evidence of product
contamination by the previous infusion prepared in
the isolator, and for this reason, the effectiveness of
455
SECTION FOUR Dispensing and related pharmaceutical practice activities
Figure 40.4*Tevadaptor closed cytotoxic reconstitution and fluid transfer system. (Courtesy of Teva Hospitals.)
cleaning procedures should be validated. This can be
done using simulations with fluorescent dyes replacing the cytotoxic drug, and using a UV lamp after
the cleaning process to visualize any remaining fluorescent residues. However, a more robust validation
would include deliberate contamination by three or
four ‘marker drugs’ from different chemical classes,
where wipe samples are analysed after cleaning to
detect any low levels of drug residues that persist.
with a cytotoxic spillage. In the event of a spillage, the
problem should be dealt with immediately to prevent
the spread of contamination. A written policy on dealing with spillages should be prepared and the operator
should be fully competent in the implementation of
this. Most policies are based on a spillage kit which
contains all the required materials to deal with a spill.
These include an absorbent cloth to wipe up liquid
spillage and booms to contain a large volume spillage.
Spillage involving a powder should be wiped up using
a damp cloth to ensure that inhalation of powder
Dealing with cytotoxic spillage
particulates does not occur. Contaminated cloths
should be disposed of in a cytotoxic hazardous waste
During reconstitution or manipulation, operators
must be aware of the procedures required for dealing
456
bag or cytotoxics sharps bin. All surface areas contam-
inated by the spillage should be washed with copious
Specialized services CHAPTER 40
amounts of water (sterile water is available in the
spillage kit). Cytotoxic spillage kits should be available in pharmacy preparation units, on chemotherapy
wards and clinics and in vehicles used to transport
cytotoxic medicines.
If the spillage has come in contact with the skin,
the contaminated area should be washed thoroughly
with soap and water. Contact with eyes should
be dealt with by irrigation with a sodium chloride
eyewash, the incident reported and medical help
sought. In the event of a needle-stick injury involving
direct contact with a cytotoxic agent, the puncture
wound should be encouraged to bleed and the area
should again be thoroughly washed. All accidents
involving spillage or needle-stick injury should be
reported.
Disposal of cytotoxic waste
Cytotoxic waste materials are regarded as ‘hazardous
waste’ and should be placed in a purple coloured
plastic bag, sealed and labelled with a cytotoxic warning label ready for disposal by incineration. Sharp
objects including needles, syringes, ampoules and
vials should be placed in a sharps bin which is made
of rigid plastic and does not allow leakage of cytotoxic
waste. When the sharps bin is full, it should be sealed
with ‘cytotoxic’ warning tape and disposed of by incineration. Operators should never put their hands or
fingers into a sharps bin, and sharps bins should not be
over-filled.
Nursing staff have the task of handling excreta of
patients who have received cytotoxic medicines. The
potential risks involved will vary depending on the
cytotoxic medicine used, dosage given, route of administration and the type of elimination profile.
Reports suggest that excreta should be assumed to
be potentially hazardous for at least 48 hours after
cytotoxic administration is complete. Ward staff
should be made fully aware of the patients who pose
this risk and should always take the necessary handling precautions, for example wearing chemotherapy
gowns and gloves. Patients receiving chemotherapy in
the outpatient clinic should have the use of a designated toilet to minimize the spread of contamination.
For patients receiving home chemotherapy, family
members should be warned about the potential
hazards and advised to exercise extreme caution when
handling excreta from the patient. The Cytotoxics
Handbook (Allwood et al 2002) contains useful
information on the persistence of cytotoxic drugs in
patient excreta.
Packaging of cytotoxic
infusions
As a minimum, cytotoxic infusions in syringes or infusion bags should be packaged in a labelled, hermetically sealed overwrap. This has two functions:
containment of any leak from the infusion and protection of portering and nursing staff from any cytotoxic residues on the surface of infusion bags and
syringes. Ideally (and essentially for transport over
long distances), the infusions, in sealed overwraps,
should be transported to wards and clinics in a rigid,
closed plastic box to provide further protection from
any mechanical trauma.
Management of the
chemotherapy workload
It is evident from the above text that chemotherapy
preparation is very labour-intensive. In recent years,
there has been a clear tendency to move from inpatient treatment of cancer patients on hospital wards
to chemotherapy outpatient clinics. The operation of
outpatient clinics can place significant workload pressures on pharmacy chemotherapy units, partly because several patients often arrive for treatment at
the same time, and also because blood test results
and other patient-specific data are required before
the oncologist is able to confirm the chemotherapy
dose and allow treatment to proceed. This often
results in several prescriptions arriving in pharmacy
at the same time and, consequently, severe delays
before some patients receive their chemotherapy on
the outpatient clinic. Such delays are not only distressing for patients and chemotherapy nurses waiting to
administer treatments, but can also result in treatments over-running normal working hours which can
limit the availability of specialist oncology staff to deal
with any treatment complications that patients may
experience.
Various strategies have been employed to manage
these problems. In many centres, it is possible to
organize patients’ GPs to take blood samples 2 days
before the patient is due to visit the outpatient clinic
for treatment. Blood counts are then available to the
oncologist before the patient arrives at the clinic for
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SECTION FOUR Dispensing and related pharmaceutical practice activities
treatment. This enables prescriptions to be ‘prewritten’ so that pharmacy can prepare batch
documents and tray-up consumables on the day before treatment, and the go-ahead for preparation can
be authorized very early on the day of treatment. Prepreparing treatments in anticipation of blood results is
not recommended, because if treatment does not
proceed, or if a dose reduction is required, significant
costs are incurred from drug wastage.
More recently, many oncology centres have
adopted the approach of ‘dose-banding’. Individual
patient doses are calculated in the normal way, but
the dose is then fitted to predefined dose ranges or
‘bands’. If for a given drug the predefined bands were
100–110 mg, 110–120 mg, 120–130 mg, etc. then,
for example, a calculated dose of 113 mg would be
fitted to the middle band of 110–120 mg. The dose
provided to the patient is standardized for each band,
normally at the mid-point of the band. So in this
example, the standard dose provided would be
115 mg. The key point about dose-banding is that
these standard doses are provided with a limited range
of standard pre-filled syringes or infusion bags, either
singly or in combination. In practice, five or six standard pre-fills are needed to provide the required range
of standard doses. Depending on the validated shelf
life, these standard pre-fills can be batch prepared,
and a stock of them can be stored on the outpatient
clinic for immediate dispensing when required. In
many centres, this approach has reduced both patient
waiting times and drug wastage to almost zero. Further advantages of this approach are that the batches
of standard pre-filled syringes or bags can be prepared
according to planned work schedules and may also be
subjected to prospective QC testing prior to release.
Not only is the workload planned and controlled, but
quality and patient safety can be improved also. Dosebanding has been widely accepted by oncologists in
the UK, largely because the maximum variation of the
administered dose from the prescribed dose is limited
to <5%.
There is no doubt that managing chemotherapy
services is a very challenging task. Operating a
patient-focused service which meets clinical needs
within the confines of limited resources requires
innovation, organization and regular communication
with medical and nursing colleagues. The service
should be carefully monitored and key outcomes such
as errors and patient waiting times should be audited
on a regular basis. Requests for new work should
be handled efficiently, but a capacity plan to define
safe workload limits must be in place to ensure that
the service does not become overstretched and compromise patient safety.
Administration of cytotoxic medicines
Specialist chemotherapy nurses are usually responsible for administration of chemotherapy on the oncology or haematology ward and in the outpatient clinic.
Some highly specialized, high-risk infusions (e.g. intrathecal and intra-arterial) are still administered by
medical staff. Cytotoxic infusions are normally infused using electronic pumps, some of which provide
a full audit trail of the infusion time, rate and volume
delivered. For many drugs, the chemotherapy infusions are vesicant and can severely damage the lining
of blood vessels and blood cells. To reduce such damage, these drugs are infused into a central vein (e.g.
cephalic and vena cava) where there is a high blood
flow to ensure rapid dilution of the drug infusion.
Placing a central venous catheter into a patient is
not a trivial procedure and is usually carried out in
an operating theatre by an experienced anaesthetist.
An alternative is the placement of a peripherally
inserted central catheter (PICC), which is tunnelled
to a central vein via peripheral veins and can be
inserted by a trained nurse in the clinic.
A potential complication of chemotherapy administration occurs when the tip of the catheter used for
drug administration locates in the tissues instead of
the lumen of the vein. This is known as ‘extravasation’
or ‘tissuing’ and can cause extremely serious tissue
damage which, in extreme cases, can require the
amputation of the limb. In the event of extravasation
occurring, administration is halted immediately for
staff to aspirate infusion from the tissues and carry
out locally agreed policies and procedures which
involve, for example, the administration of steroids
to reduce tissue inflammation. Extravasation kits
should be available on hand in the ward or clinic in
anticipation of this problem.
Administration of chemotherapy is clearly a complex and potentially dangerous procedure. National
Cancer Standards define the qualification and experience of staff engaged in all aspects of cancer treatment, including drug administration. The NPSA 20
Alert on injectable medicines will place the administration of chemotherapy under particular scrutiny,
and will further ensure that only experienced and
competent staff are permitted to administer these
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