2.

Preparing for
Cytotoxic Production
 2.1. Introduction to Cytotoxic drugs

Cytotoxic drugs are known to be highly toxic to cells,

mainly through their action on cell reproduction.

Many have proved to be carcinogenic, mutagenic or

teratogenic.

These drugs are increasingly being used in a variety of health

care settings for the treatment of cancer and other medical
conditions such as rheumatoid arthritis, multiple sclerosis and
auto-immune disorders.

2
Many anti-cancer agents are toxic to normal dividing cells,
particularly those in the bone marrow, gastrointestinal tract,
gonads, skin and hair follicles.

The number of cytotoxic drugs available has expanded rapidly and

their cellular and biochemical effects are now better defined,
facilitating rational drug combinations.

3
2.1.1. Pathophysiology of cancer

• Cancer
Cancer is a group of more than 100 different diseases
Characterized by
uncontrolled cellular growth, local tissue invasion, and distant
metastases
• Neoplasm
• A mass of tissue formed as a result of
• Abnormal
• Excessive
• Uncoordinated
• Autonomous and
• purposeless Proliferation of cells

4
It is one of the major causes of death in developed nations
atleast 1 in 5 of the population of Europe and north America can
expect to die of cancer.
Cancers are more common in aged people.
As life expectancy is increasing the incidence of cancers is also
increasing.
With the present methods of treatment one third of the patients
are cured with local modalities of treatment (surgery or
irradiation therapy) which are quite effective when the tumor
has not metastasized.

5
In metastasis systemic chemotherapy is required along
with surgery or irradiation.
At present 50 % of the patients of cancer can be treated
with chemotherapy contributing to cure in 10 -15% of
the patients.
The terms cancer, malignant neoplasm and
malignant tumor are synonymous

6
• Cancer occurs after normal cells have been
transformed into neoplastic cells through alteration
of their genetic material and the abnormal
expression of certain genes.

• Neoplastic cells usually exhibit chromosomal

abnormalities and the loss of their differentiated

properties.
7
These changes lead to uncontrolled cell division and many
result in the invasion of previously unaffected organs, a
process called metastasis.
 Malignant disease accounts for a high proportion of deaths in
industrialized countries.
 The treatment of anticancer drug is to give palliation,
reduce remission and, if possible, cure.

8
9
 Environmental Carcinogens

•A cancer-causing agent

•Three main types:

• Chemical
• Physical (radiation)
• Biological (especially virus)
 Chemical Carcinogens

•Direct-acting

•Indirect-acting (must be metabolized to activated

metabolic forms)
 Electrophiles

•Direct-acting carcinogens are already electrophilic

•Indirect-acting carcinogens are metabolically

activated into electrophilic species
Electrophilic Theory of Chemical Carcinogenesis

•Electrophilic (electron-seeking) molecules will bind to

nucleophilic (electron-rich) macromolecules in the cell
• DNA
• RNA
• Proteins

13
 Direct-acting Carcinogens

•Nitrogen mustard

•Nitrosomethylurea

•Benzyl chloride
 Indirect-acting Carcinogens

•Polycyclic aromatic hydrocarbons (PAH)

•Produced by incomplete combustion of organic

materials

•Present in chimney soot, charcoal-grilled meats, auto

exhaust, cigarette smoke
Polycyclic aromatic hydrocarbons causing cancer

Benzofluoranthenphenanthren

Benzofluoranthennaphthalene

Anthracene fluoranthene

Benzo anthracene fluoranthene

16
Human carcinogens - environmental

• Aflatoxins • Creosote (fosil fuel)

• Asbestos • DDT

• Benzene • Polycyclic aromatic

• Cadmium hydrocarbons

• Coal tar • Radon

• Solar radiation
Human carcinogens - drugs/therapeutic agents

• Adriamycin • Diethylstilbestrol
(doxorubicin) • Ethylene oxide
• Androgenic steroids • Melphalan
• Chlorambucil • Tamoxifen
• Cisplatin

• Cyclophosphamide

• Cyclosporin A
Physical Carcinogens

• Ultraviolet light

• Ionizing radiation (X-rays)

• Asbestos
Ionizing Radiation

•Death of pioneer radiation researchers from neoplasms

•High incidence of leukemia among radiologists

recognized in 1940s

•Osteosarcoma incidence in radium dial painters

Viral Carcinogenesis

•Viral infections account for an estimated one in seven

human cancers worldwide

•Majority of these are due to infection with two DNA

viruses
• HBV - linked to hepatocellular carcinoma
• HPV - linked to cervical carcinoma
Oncogenic Viruses

•Human papillomaviruses - HPV

•Epstein-Barr Virus (EBV)

•Human herpesvirus 8 (HHV8)

•Hepatitis B virus - HBV

•Hepatitis C virus - HCV

How Do Viruses like HPV and HBV Cause Cancer?

•Very small viruses

•Can integrate their viral DNA into host genome

•They code for viral proteins which block tumor

suppressor proteins in cells
Treatment options of cancer:

• Surgery

• Radiotherapy

• Chemotherapy

• Immunotherapy and Gene therapy

24
The Classification of Anticancer Drugs

1. According to chemical structure and source of the

drug;

2. According to biochemistry mechanisms of

anticancer action

3. According to the cycle or phase specificity of the

drug

25
The Classification of Anticancer Drugs

According to chemical structure and source of the

drug:
 Alkylating Agents,
Antimetabolite,
Antibiotics,
Plant Extracts ，
Hormones ， Others.

26
The Classification of Anticancer Drugs

According to biochemistry mechanisms of anticancer

action:
 Block nucleic acid biosynthesis
 Direct influence the structure and function of DNA
 Interfere transcription and block RNA synthesis
 Interfere protein synthesis and function
 Influence hormone homeostasis
 Others
27
The Classification of Anticancer Drugs

According to the cycle or phase specificity of the drug:

 Cell cycle nonspecific agents (CCNSA)

 Cell cycle specific agents (CCSA)

28
The Basic Concept of Cell Generation Cycle

•The cycle of cell replication includes:

M （ Mitosis ） phase

G1 （ Gap1, period before S ） phase

S （ DNA synthesis ） phase

G2 （ Gap2,period after S ） phase

29
Cell Cycle Nonspecific Agents (CCNSA)

drugs that are active throughout the cell cycle


Alkylating Agents

Platinum Compounds

Antibiotics

30
Cell Cycle Specific Agents (CCSA)

Drugs that act during a specific phase of the cell cycle

S Phase Specific Drug:

antimetabolites, Topoisomerase Inhibitors

M Phase Specific Drug:

Vinca Alkaloids, Taxanes

G2 Phase Specific Drug:

bleomycin
31
32
Mechanism of Anticancer Drugs

• Block nucleic acid (DNA, RNA) biosynthesis

• Directly destroy DNA and inhibit DNA reproduction

• Interfere transcription and block RNA synthesis

• Interfere protein synthesis and function

• Influence hormone homeostasis

33
Block Nucleic Acid (DNA, RNA) Biosynthesis

Antimetabolites:

• Folic Acid Antagonist:

• Pyrimidine Antagonist:

• Purine Antagonist

34
Interfere Protein Synthesis

•Antitubulin: vinca alkaloids and taxanes;

•Interfere the function of ribosome: harringtonines ；

•Influence amino acid supply: L-asparaginase

35
Interfere Transcription and Block RNA Synthesis

• Bind with DNA to block RNA production.

doxorubicin

36
Influence the Structure and Function of DNA

• Alkylating Agent: mechlorethamine, cyclophosphamide

and thiotepa

• Platinum: cis-platinium

• Antibiotic: bleomycin and mitomycin C

• Topoisomerase inhibitor: camptothecine and

podophyllotoxin

37
 Anticancer Drugs

• Alkaloid
• Alkylating Agent
• Hormones
• Antimetabolite • Others （ cis-platinum ， carboplatin ，
lobaplatin ）
• Antibiotics

38
39
 Alkylating Agents
Mechanism of Action
• Alkylate within DNA at the N7 position of guanine
Resulting in miscoding through abnormal base-
pairing with thymine or in depurination by
excision of guanine residues, leading to
strand breakage
The specific type of chemical bonding involved is
alkylation.

40
41
• Cyclophosphamide and ifosfamide are widely used in
the treatment of hematological malignancies and solid
tumours including:
• Breast
• Lung
• Prostate cancer
• Ovarian cancer
• Lymphomas and multiple myeloma

42
• Cyclophosphamide and Ifosfamide are prodrugs and
must be oxidized by CYP3A5 and CYP2B6 oxidase to
acquire an antineoplastc activity through formation of
Phosphoramide mustard and Ifosfamide Mustard
which react with DNA to form covalent bonds,
causing single-strand or double strand DNA breaks

43
Alkylating Agents——Cyclophosphamide
Indications ：
 It is used in the treatment of chronic lymphocytic leukemia, non-
Hodgkin’s lymphomas, breast and ovarian cancer, and a variety of
other cancers.
 It is also a potent immunosuppressant, it is used in the
management of rheumatoid disorders and autoimmune nephritis.
 Cyclophosphamide can also be given orally

44
Resistance of Alkylating Agents

Resistance to alkylating agents has several causes:

 Membrane transport may be decreased.

 The drug may be metabolized to inactive species.

45
Adverse Effects of Alkylating Agents

• Myelosuppression is the dose-limiting adverse effect for

alkylating agents.

• Nausea and vomiting are common as are teratogens and

gonadal atrophy, although in the latter cases these are
variable, according to the drug, its schedule, and route of
administration.

• Treatment also carries a major risk of leukemogenesis

and carcinogenesis.
46
Alkylating Agents——Nitrosoureas

Carmustine, Lomustine, Semustine

Pharmacokinetics:

• Nitrosoureas are highly lipophilic and reach cerebrospinal

fluid concentrations that are about 30% of plasma
concentrations.

Indications:

• Because of their excellent CNS penetration, carmustine

and lomustine have been used to treat brain tumors. 47
Alkylating Agents— Phenylalanine Nitrogen Mustard

•Melphalan is a nitrogen mustard that is primarily used to

treat multiple myeloma (plasma cell myeloma), breast
cancer, and ovarian cancer.

48
Alkylating Agents— Alkysulfonates

Busulfan [Myleran]

Indications:

• Busulfan is administered orally to treat chroic

granulocytic leukemia and other myeloproliferative
disorders.

49
Alkylating Agents——Thiotepa

 Thiotepa is converted rapidly by liver mixed-function

oxidases to its active metabolite

Triethylenephosphoramide (TEPA); it is active in

bladder cancer.

50
51
 Antimetabolites

General Characteristics ：

 Antimetabolites are S phase-specific drugs that are

structural analogues of essential metabolites and that
interfere with DNA synthesis.

 Myelosuppression is the dose-limiting toxicity for all

drugs in this class.

52
Classification of Antimetabolites

 Folic acid Antagonists

 Purine Antagonists

 Pyrimidine Antagonist

53
Antimetabolites—Folic Acid Antagonist

Methotrexate （ MTX ）

Mechanism of Action ：

 The structures of MTX and folic acid are similar. MTX is

actively transported into mammalian cells and inhibits
dihydrofolate reductase, the enzyme that normally
converts dietary folate to the tetrahydrofolate form
required for thymidine and purine synthesis.

54
Antimetabolites—Folic Acid Antagonist
Methotrexate （ MTX ）

Indications ：

• The use of MTX in the treatment of choriocarinoma, a

trophoblastic tumor, was the first demonstration of
curative chemotherapy.

• It is especially effective for treating acute lymphocytic

leukemia and for treating the meningeal metastases of a
wide range of tumors.
55
Antimetabolites—Folic Acid Antagonist

Methotrexate （ MTX ）

Adverse Effects ：
MTX is myelosuppressive, producing severe leukopenia,
bone marrow aplasia, and thrombocytopenia.
This agent may produce severe gastrointestinal
disturbances.
Renal toxicity may occur because of precipitation
(crystalluria) of the 7-OH metabolite of MTX. 56
leucovorin

Intentional high doses (or overdoses) of methotrexate

can be corrected by administration of leucovorin.

Leucovorin bypasses the enzymatic step inhibited by

methotrexate and supplies the folate cycle with an
intermediate molecule that possesses a carbon moiety at
the correct oxidation state for further metabolism in the
cycle.
57
58
59
Antimetabolites—Purine Antagonists

6-Mercapapurine （ 6-MP ）

The drugs are believed to act similarly to inhibit purine

base synthesis, although their exact mechanisms of
action are still uncertain.

Indications:

• Mercaptopurine is used primarily for the maintenance of

remission in patients with acute lymphocytic leukemia
and is given in combination with MTX for this purpose. 60
• Mechanism:
Mechanism Mimic of hypoxanthine, the
precursor to adenine and guanine; inhibit purine
synthesis. Specifically competes with
hypoxanthine and guanine for the enzyme
hypoxanthine-guanine
phosphoribosyltransferase (HGPRTase)

61
62
 Adverse Effects

• Well tolerate.

• Myelosuppression is generally mild.

• Long-term mercaptopurine use may cause

hepatotoxicity.

63
Antimetabolites——Pyrimidine Antagonists

5-Fluorouracil (5-FU)

Mechanism of Action ：
• Fluorouracil is an analogue of thymine in which the methyl group is
replaced by a fluorine atom. It has two active metabolites: 5-FdUMP
and 5-FdUTP.

• 5-FdUMP inhibits thymidylate synthetases and prevents the

synthesis of thymidine, a major building block of DNA.

• 5-FdUTP is incorporated into RNA by RNA polymerase and

interferes with RNA function. 64
 Antimetabolites——Pyrimidine Antagonists

5-Fluorouracil (5-FU)

Indications ：

• Fluorouracil is exclusively used to treat solid tumors, especially

breast, colorectal, and gastric tumors and squamous cell tumors of
the head and neck.

65
Antimetabolites—Pyrimidine Antagonists

5-Fluorouracil (5-FU)

Adverse Effects ：

• Fluorouracil may cause nausea and vomiting,

myelosuppression, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.

• With fluorouracil, myelosuppression is more

problematic after bolus injections, whereas mucosal
damage is dose-limiting with continuous infusions. 66
 Antimetabolites——Pyrimidine Antagonists

Cytarabine
Mechanism Inhibitor of DNA polymerase; gets incorporated in DNA
efficiently but then prevents continued elongation of DNA strands .

Indications ：
• Cytarabine has a narrow clinical spectrum and is primarily used in combination
with daunorubicin or thioguanine for the treatment of acute nonlymphocytic
leukemia.

Adverse Effects:
• High doses of cytarabine can damage the liver, heart, and other organs.

67
 Antibiotics

Classification of Antibiotics:

• Adriamycin

• Mitomycin C

• Bleomycin

• Actinomycin D

• All these drugs must be administered IV, because they

are inactivated in the GI tract
68
Antibiotics
Adriamycin and Daunorubicin ：
Properties:
• Adriamycin and Daunorubicin are tetracycline rings with the sugar
daunosamine.
• They block the synthesis of DNA and RNA.
• These agents are primarily toxic during the S phase of cell cycle.
• These agents imparts a red tinge to the urine.
• Adramycin is used to treat acute leukemias, lymphoma, and a
number of solid tumors.
69
 Antibiotics
Mitomycin C:

Mechanism:

• Mitomycin C is an antineoplastic antibiotic that alkylates DNA and

thereby causes strand breakage and inhibition of DNA synthesis.

Indications:

• It is primarily used in combination with vinvristine as therapy for breast

cancer.

Adverse Effects:

• Mitomycin produces delays and prolonged myelosuppression that

preferentially affects platelets and leukocytes. 70
Antibiotics

Actinomycin D:
• Actinomycin D prevents DNA transcription and messenger
RNA synthesis.

• The drug is given intravenously, and its clinical use is limited to

the treatment of trophoblastic (gestational) tumors and the
treatment of pediatric tumors, such as Wilms’ tumor and Ewing’s
sarcoma.

71
 Antibiotics
Bleomycin:

Mechanism:

• The drug has its greatest effect on neoplastic cell in the G2 phase of the cell
replication cycle.
• Although bleomycin intercalates DNA, the major cytotoxicity is believed to result
from iron catalyzed free radical formation and DNA strand breakage.

Indications:
• It is useful in Hodgkin’s and non-Hodgkin’s lymphomas, testicular cancer, and
several other solid tumors.

Adverse Effects:
• Bleomycin produces very little myelosuppression. The most serious toxicities of
Bleomycin are pulmonary and mucocutaneous reactions. 72
Anti-Cancer Plant Allaloids
• Tubulin-Binding Agents

Vinca Alkaloids: The cellular mechanism of action of

vinca alkaloids is the prevention of microtubule
assembly, causing cells to arrest in the late G2 phase by
preventing formation of mitotic filaments for nuclear
and cell division.

73
 Microtubules are intracellular organelles formed from the protein
tubulin.

These organelles have a number of essential cellular functions

including :

chromosome segregation,

the maintenance of cell shape,

transport, motility, and

 organelle distribution.

• Drugs that affect the tubulin-microtubule equilibrium (taxol, vinca

alkaloids) are effective anticancer drugs.
74
Anti-Cancer Plant Allaloids

• Tubulin-Binding Agents,Vinca alkaloids:

Vinblastine,vincristin, vindesine and vinorelbine are all

alkaloids derived from the periwinkle plant (Vinca rosea).

Indications:
• Vinblastine is used in combination with Bleomycin and Cisplatin
for metastatic testicular tumors.
Toxicity includes
• nausea and vomiting, bone marrow suppression, and
alopecia

75
• Vincristine is used in combination with
prednisone to induce remission in childhood
leukemia.
• S/E
muscle weakness,
peripheral neuritis, paralytic
 mild bone marrow depression,
alopecia

76
•Vinorelbine is used to treat non-small-
cell lung cancer and breast cancer.
•S/E
•Bone marrow suppression,
•fatigue, constipation,
•hyporeflexia, paresthesias

77
Anti-Cancer Plant Allaloids

• Tubulin-Binding Agents

• Taxanes:

Taxanes enhance all aspects of tubulin polymerization, an

action that is the opposite to that of vinca alkaloids, but
they are also cytotoxic, emphasizing the dynamic
importance of tubulin polymerization as a target for
cytotoxic drugs.

Paclitaxel, Taxotere
78
• The drug functions as a mitotic spindle poison through
high-affinity binding to microtubules with enhancement
of tubulin polymerization.
• This promotion of microtubule assembly by paclitaxel
occurs in the absence of microtubule-associated
proteins and guanosine triphosphate and results in
inhibition of mitosis and cell division
• SE
• Hypersensitivity reactions may be observed in up to 5%
of patients, but the incidence can be reduced by
premedication with dexamethasone, diphenhydramine,
and an H2 blocker.

79
 Platinum Compound
Cisplatin:

Mechanism of Action:
• the precise mechanism of action of cisplatin is still
undefined, it is thought to act in somewhat the same
way as alkylating agents.
• It kills cells in all stages of the cell cycle,
• inhibits DNA biosynthesis, and binds DNA through
the formation of interstrand cross-links. The primary
binding site is the N7 of guanine,.
• The platinum complexes appear to synergize with
certain other anticancer drugs.
80
 Platinum Compound
Cisplatin:
Indications:

• Cisplatin has efficacy against a wide range of neoplasms. It is given

intravenously as a first-line drug for testicular, ovarian, and bladder
cancer, and it is also useful in the treatment of melanoma and a
number of other soild tumors.

Adverse Effect:

• Cisplatin produces relatively little myelosuppression but can cause

severe nausea, vomiting, and nephrotoxicity.
81
• Aggressive hydration with intravenous saline
infusion alone or with saline and mannitol or
other diuretics appears to significantly reduce
the incidence of nephrotoxicity.

82
Platinum Compound

Carboplatin:
• Carboplatin is a second-generation platinum analog that
exerts its cytotoxic effects exactly as cisplatin and has
activity against the same spectrum of solid tumors.
• Its main dose-limiting toxicity is myelosuppression, and
it has significantly less renal toxicity and gastrointestinal
toxicity than cisplatin.
• Moreover, vigorous intravenously hydration is not
required. As a result, carboplatin is now being used in
place of cisplatin in combination chemotherapy

83
Hormones

• Several types of hormone-dependent cancer (especially breast,

prostate, and endometrial cancer) respond to treatment with their
corresponding hormone antagonists.

• Estrogen antagonists are primarily used in the treatment of breast

cancer, whereas androgen antagonists are used in the treatment of
prostate cancer.

• Corticosteroids are particularly useful in treating lymphocytic

leukemias and lymphomas.

84
Hormones

Estrogens:

• Estrogens inhibit the effects of endogenous androgens

and androgen-dependent metastatic prostatic carcinoma.
Diethylstilbestrol is usually the agent of choice.

• Cardiac and cerebrovascular complications and

carcinoma of the male breast are potential adverse
effects.

85
Hormones

Progenstins:

• Progestins are useful in the management of endometrial

carcinoma and back-up therapy for metastatic hormone-
dependent breast cancer.

86
Hormones

Antiestrogen: Tamoxifen

• Tamoxifen is the drug of choice in postmenopausal

women with or recovering from metastatic breast cancer.
It is most effective in patients who have estrogen receptor-
positive tumors.

• Tamoxifen is also used as adjunvctive therapy to

oophorectomy to leuprolide or goserelin in premenopausal
women with estrogen receptor-positive tumors.
87
Hormones
Androgens:

• Androgen activity in breast cancer is similar to that of

estrogens, perhaps for the same mechanistic reasons.

• Virilizing effects and hepatic toxicity make them

unacceptable to most patients.

• Fluoxymesterone is the most widely used agent.

• Danazol has use in hematology in aplastic anemia and

congenital anemias. 88
Hormones
Glucocorticoids:

• They are integral components of curative therapy for

acute lymphoblastic leukemia, non-Hodgkin’s
lymphoma, and Hodgkin’s disease.

• Glucocorticoids have essential roles in the prevention of

allergic reaction, emesis control, relief of intracranial
hypertension or spinal cord compression in neurologic
complications, and pain relief.
89
Thanks
!
90
 5.2. Production method of Cytotoxic drugs
 Before actually preparing the cytostatic
mixture, the following activities have been
identified.

 put on special protective clothing including

non-sterile examination gloves.

91
 During the unpacking or handling of the vials,
the healthcare worker’s hand should be
protected as the outside surface of the vials
might be contaminated with cytotoxic drugs.
 Disinfect the work area.
 Assemble and disinfect all material necessary
to prepare the Cytotoxic drugs.

92
 Similar care should be taken in the
preparation, administration and disposal of
chemotherapy drugs.
 In addition to healthcare professionals, patients
and persons that are directly involved in home
care should also be educated safety standards
and guidelines.

93
 Always wear gloves when handling the drug.
 Avoid touching the drug.
 Wash hands before putting gloves on and after
wearing gloves.
 Gloves used for protection against
chemotherapy drugs must be selected,
specifically for the type of chemicals used.

94
 Use medical grade, sterile or non-sterile, gloves
depending on the technique recommended by
your healthcare facility.
 Always use powder-free gloves. Glove powders
may contaminate chemotherapy work area.
 Choose a natural rubber latex, nitrile or neoprene
glove - Polyvinyl chloride (PVC) gloves are not
recommended for handling chemotherapy drugs.
 Double gloving is strongly advised when there is
a risk of exposure during preparation or
administration of chemotherapy drugs.

95
 Before handling chemotherapy drugs
- Observe gloves for any break in barrier.
- Change gloves after each use, tear,
and puncture or medication spill or after 30
minutes of wear.
 Upon removal, both gloves need to be turned
inside-out.
 Never flick, snap, or toss your gloves.
 Follow recommendations implemented by
your healthcare facility for the disposal of
gloves.

96
 Now you are ready for the reconstitution of the
Cytotoxic mixture and transfer it to the
perfusion set.
 put on sterile gloves.
 Disinfection of procedure material.
 Reconstitution of the Cytotoxic mixture.
 Perform a final disinfection of end product.
 Pack the product and label it.

97
• Specific standard operating procedures for non-
parenteral preparations (extemporaneous) include:
¥ using purpose-dedicated equipment
¥ making mixtures by dispersing tablets in water
¥ not crushing tablets in an open mortar
¥ counting tablets or capsules by machine
¥ cleaning equipment immediately after use with a
strong alkaline detergent with pH>10.

98
Drug preparation facilities

 Cytotoxic drugs should be prepared in a purpose-

designed clean room suite consisting of:
a cytotoxic clean room that houses a laminar-flow
cytotoxic drug safety cabinet or pharmaceutical
isolator for drug preparation
 A secondary barrier to prevent cytotoxic drugs
contamination of the outside environment should
be provided by High Efficiency Particulate Air
(HEPA) filters that supply filtered air to the clean
room and the anteroom.
99
Drug packaging
 Cytotoxic drugs should be packaged in a
labelled, sealed, leak-proof container, with
outer bags heat-sealed where possible,
ensuring the container:
 offers protection from light where required
protects the drugs from breakage in transit
contains leakage if breakage occurs
 has a childproof lid (if appropriate).

100
Drug transport
• Containers used for transporting prepared
cytotoxic drugs should be:
 hard-walled and robust
 made from moulded foam or other suitable
packaging material capable of protecting the
product from a shock equivalent to a drop of
one meter onto a concrete surface
 securely closed and labelled with cytotoxic
warnings.
101
Patient care equipment
 Suitable equipment designed to reduce the risk
of exposure should be employed.
 The following equipment is recommended:
¥ spill kit,
¥ strong alkaline detergent with pH>10
¥ container for spills, where access to a waste
outlet is not available
¥ approved container for sharps, where required.

102
• Standard operating procedures
The following standard operating procedures
should be adopted:
 avoid skin contact with patient body
substances
 prevent the generation of aerosols when
handling patients' vomitus, blood, excreta and
fluid drained from body cavities
contain and clean up spills immediately

103
dispose waste such as urine, faeces, vomitus, the
contents of colostomy/urostomy bags,
incontinence aids and disposable nappies,
 document the need to implement cytotoxic
precautions when handling body waste during
the period of drug excretion. Verbally advise all
staff caring for the patient.
alert careers by providing written instructions to
patients and careers for dealing with spills in the
home, and information on spill kit contents

104
 5.3. FMHACA Standards for preparation of Cytotoxic drugs

• Personnel
 All pharmacy personnel involved in any aspect of
Cytotoxic agent handling shall be trained in appropriate
handling techniques, preparation, reconstitution,
administration and disposal of Cytotoxic agents.
 Staff shall demonstrate knowledge, understanding of
and competence in these techniques prior to working
with Cytotoxic agents and regularly thereafter.
 Evaluation of aseptic technique shall include direct
observation, on-the-job performance and aseptic
technique testing.

105
All pharmacy staff shall be informed about the
health hazards of working with Cytotoxic agents,
and handling of Cytotoxic agents by pregnant,
breastfeeding women.
The effect of exposure to hazardous drugs on
human reproduction is not fully understood.
The pharmacy shall implement and maintain
Cytotoxic agent handling records and ensure the
availability of a medical surveillance program for
all staff routinely handling Cytotoxic agents.
106
• Apparel
All personnel handling Cytotoxic agents shall
wash their hands before and after the
preparation session and wear protective
clothing as described in the Sterile Product
Preparation Standard however the disposable,
powder free gloves should be changed hourly
or when contaminated or punctured.

107
• Hygiene
Strict hygiene procedures must be developed
and followed when handling cytotoxic drugs.
Eating, drinking, chewing gum and the
application of cosmetics must be strictly
prohibited.
In addition, personnel in the preparation
facility should not wear jewellery.

108
• Area
Cytotoxic agents shall be prepared in an
appropriately designed area, isolated from
general traffic to minimize air turbulence.
An eyewash station should be located within 7
meters of the work area.

109
• Equipment
Biological Safety Cabinets shall be cleaned and
disinfected before and after each preparation
session with water for injection or irrigation and a
small amount of cleaner and disinfected with 70%
isopropyl alcohol before any aseptic
manipulation.
The cabinet shall be certified annually by a
qualified technician and decontaminated just prior
to each time it is turned off.
110
• Label and Packaging
Cytotoxic agents must be properly labeled as
specified in sterile product preparation and
dispensed in leak-proof packaging for
transportation.

111
• Storage
 All shelves and bins
where Cytotoxic agents
are store should designed
to minimize the risk of
breakage
 Shipments of Cytotoxic
agents must be sealed in
plastic bags, cushion in a
strong carton and labeled
on all sides with a
“Cytotoxic” warning
label.

112
 5.4. Cytotoxic spill cleaning kits
 Spills of cytotoxic drugs and waste must be enclosed
immediately as they may present a high risk of
exposure.
 Employers should develop a spill management strategy
which includes a cytotoxic spills register.
 Spills may occur wherever cytotoxic drugs and waste
are handled, stored, transported or disposed.
 People in the immediate surrounding area of a spill
should be alerted of the incident immediately and told
to stay clear, with the area being isolated.
 Ancillary workers should assist only in the containment
of a spill while alerting trained personnel.

113
• Sources of spills
 A risk assessment should identify all likely
areas where there is a risk of a cytotoxic spill.
 Spills may result in the contamination of
floors, work surfaces, equipment, bedding and
clothing as well as the patient and career/staff
member.

114
 Spills may involve:
 cytotoxic drugs in all forms – liquid, powder, broken
tablets, tablets or creams
 cytotoxic drugs spilt (or leaking) during preparation,
storage or transport of packaged drugs
 cytotoxic drugs spilt during administration or disposal
 cytotoxic drugs leaking following disposal
 cytotoxic drugs spilt or leaking during the transport of a
patient receiving drug therapy
 cytotoxic contaminated body substances
 cytotoxic contaminated waste.

115
• Cytotoxic spills
 A standard operating procedure must be
developed and maintained for the handling of
cytotoxic spills within the institution.
 When a cytotoxic spill is cleaned, all cleaning
should begin from the outside of the spill area
and gradually work towards the centre.
 All personnel who may be involved in
handling cytotoxic drugs must be given
appropriate training in the procedures to be
followed in the event of a spill.

116
• Spills within safety cabinet or isolator
 When a cytotoxic spill occurs within the safety
cabinet or isolator, work should stop and the
spill should be cleaned up immediately.
 Small spills may be easily cleaned using
absorbent gauze.
 Large spills may require a spill pillow to absorb a
larger volume of fluid.
 The area should then be washed with an
appropriately diluted strongly alkaline detergent,
rinsed thoroughly with sterile water, and then
wiped with sterile isopropyl alcohol (70%) or
other suitable agent.

117
• Spills within clean room and anteroom
 Cytotoxic clean rooms which have a positive
pressure in relation to the external environment
should be fitted with a spill switch.
 When activated, this switch will alter the
pressure differentials within the cytotoxic suite
to minimize any contamination of the external
environment.
 The switch should also be fitted with an
audible alarm to alert other staff working in
the immediate surrounding area.

118
• Spills within storeroom
 All staff working in the pharmacy store must
be trained in the procedure to be followed in
the event of both a liquid and powder
cytotoxic drug spill.
 Wherever cytotoxic drugs are stored, spill kits
with written procedures for use must be
readily available.

119
• Spills during transport
 Personnel transporting cytotoxic drugs must be
familiar with the procedure to be followed in
the event of a spill.
 When a cytotoxic spill is cleaned, all cleaning
should begin from the outside of the spill area
and gradually work towards the centre.

120
• Spill kits
 A risk assessment should be completed for each
area to determine the contents of the cytotoxic
drug spill kit.
 Locations for storing a cytotoxic drug spill kit
should be selected and clearly sign-posted.
 A cytotoxic drug spill kits contents must be
reviewed regularly to ensure its contents have
not deteriorated, have been restocked upon use
and that it remains appropriate to the designated
area.
 The kit is designed for control and management
of hazardous drug spills, including Cytotoxics.

121
• Contents of spill kit

 A spill kit should contain:

(a) Written instructions for use of the spill kit.
(b) Warning signs to alert other staff to the
hazard and isolate the area of the spill.
(c) Impermeable protective gown,
boots/overshoes, head-cover, goggles or face
shields and suitable respirator mask.

122
(d) Pair of large size gloves. May be either
gloves manufactured specifically for handling
cytotoxics (with proven resistance), or if not,
two pairs of gloves.
(e) Plastic broom and dustpan to clean up any
broken glass.
(f) Spill mat to absorb small volumes of spilled
liquid.
(g) Large quantities of swabs for absorbing and
cleaning liquid spills.

123
(h) Concentrated alkaline detergent solution.
(i) Bottled water (correct quantity for dilution of
detergent).
(j) Clearly labelled cytotoxic waste container.
(k) Spill report/incident form.
(l) Spill pillow capable of absorbing large
volumes of liquid. This may an integral part of
the spill kit or may be supplied separately
when required

124
125
5.5. Exposure hazards and mitigation requirements
related to Cytotoxic drugs

• Occupational exposure to cytotoxic drugs and

related waste may occur when:
>> preparing drugs
>> administering drugs
>> transporting drugs
>> storing drugs
>> handling patient waste
>> transporting and disposing of waste
>> cleaning up spills.
126
• Exposure may occur through:
 skin contact,
 skin absorption,
 inhalation of aerosols and drug particles,
 Ingestion and
 sharps injuries.

127
A man handling Cytotoxic drugs

128
 Potential adverse effects

• Where control measures have been inadequate,

the health effects on those who prepare and
administer cytotoxic drugs have included:
>> alterations to normal blood cell count
>> fetal loss and possible malformations in
offspring
>> fertility changes
>> abdominal pain, hair loss, nasal sores, vomiting
>> liver damage
>> contact dermatitis.

129
130
Any hazards associated with the cytotoxic
drug must be identified.
Any risks must be assessed in consultation
with employees.
Risks must be eliminated or controlled in
consultation with employees.
Trainings must be provided.
Information and supervision must be provided.
First aid and emergency procedures must be
developed.
131
• Manufacturers and importers who supply
hazardous substances to workplaces must
provide certain information about their
product.
• They are required to:
determine whether a substance is a hazardous
substance
ensure that containers of hazardous substances
are labelled with safety information.

132
 prepare and provide specific information in
the form of safety data sheets and labels to
employers who use their substances.

When hospital departments supply cytotoxic

drugs to other hospitals, or to other facilities or
services, they are considered to be suppliers.

133
• Employers, in consultation with employees:
must use information provided by
manufacturers, importers or suppliers to
identify the hazardous substances used in the
workplace,
assess the risk to health, and
control hazards to health associated with their
use.

134
• In summary, employers are required to:
obtain a copy of the manufacturer’s or
importer’s safety data sheet and ensure that it
is accessible to workers
ensure all containers of hazardous substances
are labelled according to legislation
set-up a hazardous substances register

135
• Employers and staff who handle them
occupationally have an obligation to work a risk
management plan.
• Generally, it is a process of:
consultation and communication
hazard identification
risk assessment
risk control
evaluation of control measures
continuous improvement

136
• Effective management of health and safety
involves:
>> training
>> documentation of activities
>> regular review of the management system.

137
• There is hierarchy of control/treatments (or
ranking of controls) that incorporates a best
practice approach to managing risks.
• These controls are in order of greatest
effectiveness to least effective as follows:
 Elimination
 Substitution
 Isolation
 Engineering control
 Administrative controls
 Personal protective equipment (PPE).

138
• ELIMINATION, SUBSTITUTION OR REPLACEMENT
– Complete removal of the hazard or risk OR
where total elimination is not possible, exposure
should be prevented or minimized by elimination
of certain processes. Alternatively, consider
substituting or replacing with a less hazardous
material, process or equipment
• ISOLATION – Prevention of contamination of
staff and/or environment by containing the
cytotoxic drug at its source
• ENGINEERING CONTROLS – May include
redesigning/re-engineering the workplace e.g. use
of laminar-flow cytotoxic drug safety cabinet

139
• ADMINISTRATIVE CONTROLS – May include:
introducing new work practices and development
of SOPs, education and training, cytotoxic signs
and labels
• PERSONAL PROTECTIVE EQUIPMENT (PPE)
– The use of correct PPE which is fitted correctly,
properly stored and maintained e.g. sterile
coveralls, gloves, safety eye wear, masks. These
are the least effective method of control but are
sometimes required to protect employees from
cytotoxic related hazards in the workplace
140
 The hierarchy of controls should always be
implemented from the most effective to the least
effective.
 The employer’s primary duty is to eliminate any
risk to health arising from the use of hazardous
substances.
 Where elimination of risk is not practicable,
employers must reduce the risk, so far as is
reasonably practicable.
 Employers must first consider whether the risk
can be eliminated.
 This is the most effective way of protecting the
health of employees.

141
 Employers need to ensure that all control
measures are properly used and maintained.
 They must not rely exclusively or primarily on
administrative controls or personal protective
equipment to control the risk, as these
measures depend heavily on human behavior
to be effective.
 It is important to remember that a number of
risk controls will need to be used in
combination to effectively eliminate or reduce
the risk.
142
• Emergency procedures
 Planning for emergencies is an essential part
of risk management.
 Systems should therefore be in place to
manage sharps injuries and personal
contamination.
 Any incident should be reported so that the
cause can be investigated and determined, and
follow-up action taken if required.

143
 Cytotoxic drug preparation cause the greatest
risk of occupational exposure to personnel.
 With adequate precautions, contamination of
personnel and the work environment has been
shown to be reduced.
 The risk of exposure may be reduced by
ensuring that cytotoxic drugs are prepared by
trained pharmacists or technicians in approved
facilities.

144
 Personal Protective Equipment (PPE)
1. Coveralls and gowns
• Selection considerations for coveralls or
gowns include:
should be made of impermeable material, e.g.
bonded polyethylene fibre
should have a closed front and long sleeves
with elastic cuff
should be disposable or reusable.

145
 It should be noted that reusable coveralls and
gowns have a limited life span and should be
discarded when full protection can no longer
be guaranteed by the manufacturer or supplier.
 Gowns should not be shared and care should
be taken in removal of gowns to minimize the
risk of personal contamination.
 Gowns should be used for a maximum of one
shift and contaminated garments should be
removed immediately and disposed of or
laundered as appropriate.

146
2. Gloves
 Glove use is essential and gloves must be
chosen to maximize protection by minimizing
permeability.
 Standard surgical gloves may not provide the
required level of protection due to drug and/or
carrier permeability in the case of liquid
cytotoxic drugs.

147
• Selection considerations for gloves include:
Must be long enough to cover wrist cuffs of
coveralls or gowns while arm is bent or
stretched
Should be purpose manufactured or
manufacturer recommended Disposable
Nitrite gloves are generally recommended
Latex gloves used in drug preparation should
be sterile and powder free
Polyvinyl chloride (PVC) industrial gloves can
be used for waste management activities.
148
 Individuals handling cytotoxic drugs and related
wastes should be double gloved if they are not
wearing purpose manufactured gloves.
 This can be done with two pairs of powder-free
latex gloves.
 With double gloving, both gloves must be
changed.
 Gloves should be changed at:
 intervals recommended by the manufacturer, or
 intervals of 30 minutes, or
 when punctured, torn or contaminated.

149
3. Protective eyewear
• Protective eyewear should be provided to
prevent exposure to the mucous membranes of
the eye from liquid splashes.
• Eye protection can be provided by:
 goggles or protective eyewear with side
shields
 a transparent full-face chemical splash shield
 full eye protection provided by full-face
respiratory protective equipment (RPE).
150
RPE protective eyewear

151
 A risk assessment should be used to determine
whether a worker wearing prescription glasses
should use additional protection.
 This should be taken into account in selection
and fitting of personal protective equipment.
 Reusable eyewear should be cleaned with a
neutral detergent solution and rinsed
thoroughly at the end of the shift or when
contaminated.
 Disposable eyewear should be disposed of as
cytotoxic waste.

152
4. Shoe covers and overshoes
• Selection considerations for shoe covers and
overshoes include:
shoe covers must be made of impermeable
material, e.g. bonded polyethylene fibre.
overshoes should be high enough to cover the
trouser cuff of the coverall and designed so
they do not slip down
 the soles should be made of a suitable non-
shedding material.

153
• Contaminated, non-disposable footwear
should be cleaned with a detergent solution
and rinsed thoroughly after each use, and
reusable overshoes should be stored for
laundering.
• Disposable shoe covers should be disposed of
as cytotoxic waste.

154
overshoes Shoe covers

155
5. Respiratory protective equipment (RPE)
 Suitable RPE should be selected, used, stored
and maintained.
 Selection considerations for RPE include:
 A particulate filter mask is recommended
when dealing with situations in which aerosols
may be generated.
 A requirement for a worker to wear
prescription glasses should be taken into
account in selection and fitting of RPE.
156
6. Head covering
 Head coverings should be worn to contain hair
and minimize contamination.

 They should cover exposed hair, including

beards and moustaches.

157
 Other considerations should include:
hoods should fit snugly around the face
(hooded coveralls are recommended for drug
preparation)
caps should fit tightly around the head
facial enclosures or covers should be designed
in conjunction with hoods and other coverings
hoods, caps and facial enclosures should not
interfere with respiratory protection.

158
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