MONOGRAPH FOR UKPID
CISPLATIN
Robie Kamanyire
National Poisons Information Service (London Centre)
Medical Toxicology Unit
Guy's & St Thomas' Hospital Trust
Avonley Road
London
SE14 5ER
UK
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
1 NAME
1.1 Substance
Cisplatin
1.2 Synonyms
CDDP, cis-DDP, Cis-Diamminedichloroplatinum,
cis-Diamminedichloroplatinum (II), Cis-platin, cisplatinum,
cis-Platinum, DDP, Peyrone's Chloride, Platinum Diamminodichloride,
Diaminedichloroplatinum.
1.3 Therapeutic class
Antineoplastic agent
1.4 Product Name(s)
Abiplatin (Netherlands), Cisplatin (UK), Cisplatyl (France),
Citoplatino (Italy), Lederplatin (Sweden), Neoplatin (Spain),
Norplatin (South Africa), Placis (Spain), Platamine (Australia),
Platiblastin (Germany), Platiblastine (Switzerland), Platinex
(Germany, Italy), Platinol (Canada), Plastistil (Spain), Platistin
(Sweden), Platosin (Netherlands), Pronto Platamine (Italy), Randa
(Japan).
1.5 Reference number
CAS-15663-27-1
NCI-c55776
NIOSH TP 2450000
NSC-119875
NK 801
1.6 Main manufacturers and/or importers
David Bull Laboratories, Spartan Close, Tachbrook Pk, Warwick CV34 6RS
(UK)
Pharmacia Ltd, Davy Ave, Knowlhill, Milton Keynes, MK5 8PH (UK)
Farmitalia Carlo Erba Ltd, Italia House, 23 Grosvenor Rd, St. Albans,
Hertfordshire, AL1 3AW (Australia, Germany, Italy, S.Africa, Spain,
Sweden, Switzerland, UK)
Abic (Netherlands), Bellon (France), Bristol-Myers (Spain,
Switzerland, USA), Bristol-Myers Squibb (Sweden, Switzerland), Bristol
(Canada, Germany, Italy, Netherlands), Kayaku (Japan), Neva (Sweden),
Noristan (South Africa), Pharmachemie (Netherlands), Rhone-Poulenc
(Italy), Wasserman (Spain).
1.7 Presentation/formulation
Cisplatin powder for injection: Yellowish-white freeze-dried cake in
clear glass vials containing 10mg or 50mg cisplatin. The formulation
also contains sodium chloride and mannitol.
Cisplatin solution for injection: Clear, practically colourless
solution in amber glass vials containing cisplatin 1mg/ml, sodium
chloride 9mg/ml and mannitol 1mg/ml with a pH of 3.5-4.0.
2 SUMMARY
The principal target organ for cisplatin toxicity is the kidney. This
toxicity is manifested by reduced renal function and leads to serum
electrolyte changes and pathological changes in the urine analysis.
Doses of cisplatin which produce changes in renal function may cause
no histopathological changes. Higher doses of the drug lead to
interstitial nephritis.
Cisplatin also causes bone marrow hypoplasia, is ototoxic and can
cause autonomic neuropathy. Slight changes in liver function and
histopathology are also observed following cisplatin therapy.
Excessive dosage can cause protracted nausea, vomiting and diarrhoea,
thirst and metallic taste Nephrotoxicity characterised by oliguria,
azotaemia, renal tubular acidosis and acute renal failure may occur.
Electrolyte disturbances include hypomagnesaemia, hypocalcaemia,
hypophosphataemia and hypokalaemia or hyperkalaemia. Tinnitus,
dizziness, high frequency hearing loss leading to total deafness,
decreased visual acuity, papilloedema and cortical blindness may
occur. Further neurotoxicity includes peripheral neuropathy with
numbness, tingling and decreased vibratory sensation. Autonomic
neuropathy may also occur with gait difficulties, involuntary
movements and loss of deep tendon reflexes. Central nervous system
toxicity includes confusion, extrapyramidal effects and focal
convulsions progressing to grand mal convulsions. Other reported
effects include tachycardia, hyperpnoea, acute respiratory failure,
metabolic acidosis, transient elevation of alkaline phosphatase, serum
bilirubin and AST may also occur.
Cisplatin is usually administered in hospital and the administering
clinician must monitor the patient for any signs and symptoms of
toxicity. Protracted nausea and vomiting are the initial symptoms,
nephrotoxicity characterised by oliguria, renal tubular acidosis and
acute renal failure, is cumulative and increases with the total dose
and duration of treatment. Electrolyte disturbances, particularly
hypomagnesaemia and hypocalcaemia, may occur as a result of renal
toxicity. Peripheral neuropathy occurs predominantly to the sensory
fibres, further neurotoxicity occurs in the form of ototoxicity and
visual toxicity, presenting as tinnitus, high frequency hearing loss
and decreased visual acuity. Bone marrow depression may be severe,
with decreased leucocyte and platelet counts. Anaemia is also seen.
There is no specific antidote, treatment is symptomatic and
supportive. Initially hydration is the most important aspect of
treatment, volumes of 3-4 litres per day have been used in adults,
whilst children have received 3L/m2/day (Haupt et al, 1989), to
reduce the risk of nephrotoxicity. Severe nausea and vomiting may be
managed with antiemetics (e.g. ondansetron, metoclopramide or
buspirone). Patients should be monitored closely for signs and
symptoms of toxicity, particularly ototoxicity, and changes in
cardiac, liver, renal and neurological function.
3 PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Cisplatin is a synthetic compound first described by Peyrone as a
chloride salt in 1845. It was not until 1965 when Rosenberg
accidentally generated platinum salts in bacterial culture, that their
antibiotic activity was discovered. Subsequently some of these salts
were shown to inhibit solid sarcomas in mice. Clinical trials of what
we now know as cisplatin began in 1971, and its main use is as a
cytotoxic drug.
3.2 Chemical structure
cis-Diamminedichloroplatinum
Pt(NH3)2Cl2
Molecular weight: 300.1
3.3 Physical properties
Yellowish white powder, slightly soluble in water (1 in 1000),
insoluble in alcohol; sparingly soluble in dimethylformamide. A 0.1%
solution in 0.9% saline has a pH of 4.5-6.0. The injectable
preparation has a pH of 3.5-6.2.
Unopened vials of the powder are stable at room temperature for 2
years and the reconstituted material for 20 hours at 27°C. When stored
under recommended conditions commercially available cisplatin
injection is stable for 17 months following date of manufacture;
cisplatin injection remaining in the amber vial following initial
entry is stable for 28 days when protected from light or for 7 days
when stored under fluorescent light.
The unopened vials of both freeze-dried powder and solution for
injection should be stored at room temperature and protected from
light. Solutions of cisplatin must not be cooled or refrigerated as
cooling may result in precipitation. It is recommended that diluted
infusion solutions of cisplatin be protected from light during
administration. Cisplatin is degraded on contact with aluminium, and
therefore aluminium containing equipment should not be used for
administration of cisplatin.
4 USES
4.1 Indications
Cisplatin is indicated only for the treatment of malignancies. It has
useful antitumour activity in certain solid tumours including ovarian
cancer and testicular teratoma. Other malignancies which may respond
to cisplatin therapy include cancer of the cervix, breast, head and
neck, bladder and lung (small cell). In most cases the best results
are obtained when cisplatin is used in combination with another
cytotoxic drug or combined with radiotherapy.
4.2 Therapeutic dosage
4.2.1 Adults
The usual dose regimen of cisplatin when given as a single agent is
50-120 mg/m2 by intravenous infusion once every 3 to 4 weeks or
15-20 mg/m2 by intravenous infusion daily for five consecutive days
every 3 to 4 weeks. The dosage may need to be adjusted if the drug is
used in combination with other anti-tumour chemotherapy. With multiple
drug schedules cisplatin is usually given in doses from 20 mg/m2
upward every 3 to 4 weeks.
4.2.2 Children
The usual dose regimen of cisplatin when given as a single agent is
50-120 mg/m2 by infusion once every 3 to 4 weeks or 15-20 mg/m2 by
intravenous infusion daily for five consecutive days every 3 to 4
weeks. The dosage may need to be adjusted if the drug is used in
combination with other anti-tumour chemotherapy. With multiple drug
schedules cisplatin is usually given in doses from 20 mg/m2 upward
every 3 to 4 weeks.
4.3 Contraindications
Because cisplatin is used to treat life-threatening malignancies,
contraindications to its use are only relative and must be placed in
the context of the patient's overall well-being. Contraindications
are:
1) Renal failure
2) Severe bone marrow suppression
3) Peripheral neuropathy
4) Pregnancy
5) Hearing disorders
6) Allergic or anaphylactic-like reactions to platinum containing
compounds.
5 HUMAN HEALTH EFFECTS - TOXICITY
5.1 Acute toxicity
5.1.1 Ingestion
It is now generally held that cisplatin is not thought to be absorbed
through the gastrointestinal tract (Anon, 1982), although preliminary
reports suggest that it may occur in rats and mice (Siddik et al,
1984).
5.1.2 Inhalation
No data available.
5.1.3 Dermal
Droplet exposure of the skin to antineoplastic drugs rarely causes
acute problems. Cisplatin is not absorbed through intact skin, however
dermal exposure to cisplatin has resulted in skin irritation (Khan et
al, 1975) and may cause corrosive burns.
5.1.4 Eye contact
Intravitreal injection in rabbit eyes has shown that as much as 0.1mg
can be injected without toxic effect (Grant, 1986).
5.1.5 Parenteral exposure
Cisplatin is usually given intravenously, administration via
intra-arterial (Maiese et al, 1992) and intraperitoneal (Howell et al,
1982) routes have been studied.
Excess dosage can cause protracted nausea, vomiting and diarrhoea,
thirst and metallic taste Nephrotoxicity characterised by oliguria,
azotaemia, renal tubular acidosis and acute renal failure may occur.
Electrolyte disturbances include hypomagnesaemia, hypocalcaemia,
hypophosphataemia and hypokalaemia or hyperkalaemia. Tinnitus,
dizziness, high frequency hearing loss leading to total deafness,
decreased visual acuity, papilloedema and cortical blindness may
occur. Further neurotoxicity includes peripheral neuropathy with
numbness, tingling and decreased vibratory sensation. Autonomic
neuropathy may also occur with, gait difficulties, involuntary
movements and loss of deep tendon reflexes. Central nervous system
toxicity includes confusion, extrapyramidal effects and focal
convulsions progressing to grand mal convulsions. Other reported
effects include tachycardia, hyperpnoea, acute respiratory failure,
metabolic acidosis, transient elevation of alkaline phosphatase, serum
bilirubin and AST may also occur.
5.1.6 Other
No data available.
5.2 Chronic toxicity
5.2.1 Ingestion
No data available.
5.2.2 Inhalation
No data available.
5.2.3 Dermal
No data available.
5.2.4 Eye contact
No data available.
5.2.5 Parenteral exposure
No data available.
5.2.6 Other
No data available.
5.3 Special risks
5.3.1 Pregnancy
There is positive evidence of human foetal risk. A pregnant patient
was treated with cisplatin (55mg), bleomycin (30mg), and etoposide
(165mg) (all given daily for 3 days), 1 week prior to delivery, (27
weeks gestation), for an unknown primary cancer with metastases to the
eye and liver. The mother developed profound neutropenia just prior to
delivery. On the third day after birth the 1190g infant also developed
leucopenia with neutropenia, 10 days after in utero exposure to the
antineoplastic agents. The condition resolved after 10 days. At 1 year
follow up the child was developing normally, except for moderate
bilateral hearing loss. It could not be determined whether the
sensorineural deafness was due to the maternal and/or neonatal
gentamicin therapy or to the maternal cisplatin chemotherapy (Raffles
et al, 1989).
In another case a patient received a single intravenous dose of
50mg/kg cisplatin for carcinoma of the uterine cervix at 10 weeks
gestation. Two weeks later, a radical hysterectomy was performed. The
male foetus was morphologically normal for its developmental age
(Briggs et al, 1980).
A third case of cisplatin usage during pregnancy involved a 28 year
old woman with advanced epithelial ovarian carcinoma. Following
surgical treatment at 16 weeks gestation, the patient was treated with
cisplatin, 50mg/m2 and cyclophosphamide 750mg/m2 every 21 days for
seven cycles. Labour was induced at 37-38 weeks gestation leading to
the birth of a healthy 3.27kg male. No abnormalities of the kidney,
liver, bone-marrow, or auditory-evoked potential were found at birth,
and the infant's physical and neurological growth was normal at 19
months of age (Briggs et al, 1990). Although there is evidence of
human foetal risk, from the use of cisplatin in pregnant women the
benefits from its use may be acceptable.
5.3.2 Breast feeding
Breast feeding is not recommended due to the potential risk to the
infant. A 24 year old woman with an entodermal tumour of the left
ovary was treated with cisplatin, 30mg/m2 i.v. over 4 hours daily,
for 5 consecutive days, with hyper-hydration. Etoposide and bleomycin
were also administered during this time. Breast milk and blood
collected on the third day of chemotherapy, thirty minutes before
cisplatin infusion, contained platinum concentrations of 0.9mg/L and
0.8mg/L respectively. This is a milk to plasma ration of 1:1 (De Vries
et al, 1989).
5.3.3 Enzyme deficiencies
No data available.
5.3.4 Other
No data available.
5.4 Course, prognosis, cause of death
The course of cisplatin poisoning is variable However, the initial
symptoms tend to be nausea and vomiting within 12-24 hours, often
accompanied by diarrhoea. The more moderate symptoms are impairment of
taste and speech, headache and paraesthesiae, often with hearing loss
and decreased visual acuity. Rarely visual hallucinations may also be
experienced. More severe effects can be expected within a week and are
characterised by convulsions, twitching and dystonic movements,
metabolic acidosis, coma, deafness and blindness, myelosuppression,
pyrexia and acute renal failure. Toxicity is prolonged and there is a
risk of secondary infection.
5.5 Diagnosis
Since cisplatin is usually administered in hospital the administering
clinician must monitor the patient for any signs and symptoms of
toxicity. Protracted nausea and vomiting are the initial symptoms,
nephrotoxicity characterised by oliguria, renal tubular acidosis and
acute renal failure, is cumulative and increases with the total dose
and duration of treatment. Electrolyte disturbances, particularly
hypomagnesaemia and hypocalcaemia, may occur as a result of renal
toxicity. Peripheral neuropathy occurs predominantly to the sensory
fibres, further neurotoxicity occurs in the form of ototoxicity and
visual toxicity, presenting as tinnitus, high frequency hearing loss
and decreased visual acuity. Bone marrow depression may be severe,
with decreased leucocyte and platelet counts Anaemia is also seen.
5.6 Systematic description of clinical effects
5.6.1 Cardiovascular
Cardiovascular toxicity is rare but paroxysmal supraventricular
tachycardia may occur (Fassio et al, 1986).
Another report is of 4 young men (under 30 years of age) who suffered
vascular ischaemic events, 2 patients had myocardial infarcts and the
other 2 patients cerebrovascular accidents, days to months after
receiving combination cytotoxic drug therapy including cisplatin,
(Doll et al, 1986).
5.6.2 Respiratory
Hyperpnoea and acute respiratory failure have been reported after
overdose (Fassoulaki and Pavlou, 1989).
5.6.3 Neurological
5.6.3.1 CNS
Headache, extrapyramidal disorders, impairment of taste, impairment of
speech, thirst, convulsions, loss of deep tendon reflexes, gait
difficulties, coma and retrobulbar neuritis have all been reported
(Von Hoff et al, 1979).
5.6.3.2 Peripheral nervous system
Peripheral neuropathy occurs predominantly to sensory fibres with
numbness, tingling and decreased vibration sense (Mollman, 1990).
5.6.3.3 Autonomic nervous system
Autonomic neuropathy occurs.
5.6.3.4 Skeletal and smooth muscle
Muscle twitching and tetany has been reported due to cisplatin induced
hypomagnesaemia, (Anon, 1982).
5.6.4 Gastrointestinal
Nausea, vomiting and diarrhoea are the initial features of toxicity.
5.6.5 Hepatic
Transient rises in AST and ALT, serum bilirubin, alkaline phosphatase,
prothrombin time and partial thromboplastin time (Dorr and Fritz,
1980).
5.6.6 Urinary
5.6.6.1 Renal
The kidney is the primary target organ in cisplatin toxicity.
Oliguria, azotaemia, renal tubular acidosis and acute renal failure
may occur, (Rozencweig et al, 1977)
5.6.6.2 Others
No symptoms reported.
5.6.7 Endocrine and reproductive systems
No data available.
5.6.8 Dermatological
Droplet exposure of the skin to antineoplastic drugs rarely causes
acute problems. Cisplatin is not absorbed through intact skin, however
dermal exposure to cisplatin has resulted in skin irritation, (Khan et
al, 1975) and may cause corrosive burns.
5.6.9 Eye, ears, nose, throat: local effects
Eye: decreased visual acuity, papilloedema without visual disturbance,
retrobulbar neuritis and cortical blindness (Kattah et al, 1987;
Lindeman et al, 1990).
Ears: tinnitus, high frequency hearing loss, deafness (Maiese et al,
1992).
5.6.10 Haematological
Thrombocytopenia, granulocytopenia, bone marrow aplasia and bone
marrow depression may occur. Anaemia has also been reported (Kumar and
Dua, 1987).
5.6.11 Immunological
Anaphylactic reactions may occur.
5.6.12 Metabolic
5.6.12.1 Acid-base disturbances
Metabolic acidosis or respiratory alkalosis may occur.
5.6.12.2 Fluid and electrolyte disturbances
Hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia and
hyperuricaemia may occur in the context of renal impairment.
5.6.12.3 Others
Pyrexia may occur.
5.6.13 Allergic reactions
Anaphylaxis, often characterised by bronchoconstriction, facial
oedema, hypotension and tachycardia may occur within minutes of
administration of the drug (Von Hoff et al, 1979).
5.6.14 Other clinical effects
Extravasation may occur. This is characterised by local pain, swelling
and erythema around the site of injection. Localised tissue damage
following extravasation may lead to tissue necrosis with skin
ulcerations that are difficult to heal (Bertelli, 1995).
5.6.15 Special risks
Pregnancy: there is evidence of human foetal risk (Briggs et al,
1994). The possible hazards to the foetus need to be weighed against
the expected benefit to the mother in each case.
Breast feeding: not recommended because of the potential risks to the
baby. De Vries et al (1989) found the milk to plasma ratio to be 1:1
in a 24 year old patient.
6 TOXICOLOGICAL DATA
6.1 Human data
6.1.1 Adults
No minimum lethal dose has been reported. Doses as low as 100mg/m2 in
a controlled setting have been associated with minimal toxicity (Legha
and Dimery, 1985).
6.1.2 Children
No minimum lethal dose has been reported, although a dose as low as
100mg/m2 would be expected to cause mild toxicity.
6.2 Relevant animal data
The minimum lethal dose in rhesus monkeys was 5 daily doses of
2.5mg/kg (Schaeppi et al, 1973).
The minimum lethal dose for a dog was a single intravenous injection
of 2.5mg/kg (Schaeppi et al, 1973)
The LD50 in a rat was 12mg/kg (Keller and Aggarwal, 1983).
6.3 Relevant in vitro data
In vitro cisplatin has been shown to be mutagenic in human
lymphocytes, fibroblasts and lung cells (NIOSH, 1995).
7 CARCINOGENICITY
The carcinogenic potential of cisplatin has not been fully evaluated.
It has been shown to be carcinogenic in mice and rats. In studies in
BD IX rats receiving intraperitoneal cisplatin at a dose of 1mg/kg
body weight weekly for 3 weeks, 66% of the animals died within 450
days following the first application of the drug; approximately 40% of
the deaths were related to malignancies (predominantly leukaemias and
1 renal fibrosarcoma) (McEvoy, 1995).
8 OTHER RELEVANT INFORMATION
8.1 Teratogenicity
Cisplatin is embryotoxic and teratogenic in mice and rats (Keller and
Aggarwal, 1983).
8.2 Mutagenicity
In Vitro cisplatin has been shown to be mutagenic in bacteria and
has produced chromosomal aberrations in animal cells in tissue culture
(McEvoy, 1995).
8.3 Interactions
Cisplatin is rarely used as a single agent and potential interactions
with other cytotoxic agents must be carefully evaluated before
initiating therapy.
Bleomycin: Cisplatin can increase the pulmonary toxicity of bleomycin
by decreasing its renal excretion, Cisplatin is nephrotoxic and
reduces the glomerular filtration rate so that clearance of bleomycin
is reduced (Yee et al, 1983; Bennett et al,1980).
Aminoglycoside antibiotics: The nephrotoxic effects of cisplatin are
synergistic with those of aminoglycosides and the concomitant use of
these agents should be avoided. The ototoxic and magnesium losing
effects of both also seem to be additive (Gonzalez-Vitale et al,
1978).
Cranial irradiation: Enhanced ototoxicity has been reported in
patients given cisplatin for brain tumours who had also received
cranial irradiation (Reynolds, 1993).
Ethacrynic acid: Animal studies indicate that ototoxicity can be
markedly increased by the concurrent use of cisplatin with ethacrynic
acid (McEvoy, 1995).
Anticonvulsants: Phenytoin serum levels have been shown to be markedly
reduced during concurrent treatment with some cytotoxic drugs and
convulsions can occur if the phenytoin dosage is not raised
appropriately. Similar interactions have been seen with carbamazepine
and sodium valproate (Sylvester et al, 1984).
8.4 Main adverse effects
Gastrointestinal: Nausea and vomiting.
Renal: All patients show a transient reduction in creatinine clearance
and an elevation in serum creatinine. Therefore changes in creatinine
should not be considered as evidence of significant toxicity. The
incidence of serious renal impairment is reduced by hydration.
Hypomagnesaemia: Cisplatin alters the ability of the kidney to retain
magnesium. In rare cases hypomagnesaemia may cause symptomatic
muscular irritability (Stuart-Harris et al, 1980).
Hypersensitivity: Occurs rarely and is characterised by the signs and
symptoms of anaphylaxis (Von Hoff et al, 1976).
Visual effects: Visual loss is a relatively uncommon toxic effect of
cisplatin, this has been attributed to optic neuritis and cortical
blindness (Kattah et al, 1987).
Neuropathy: Cisplatin, particularly when given at high doses can cause
a peripheral neuropathy characterised by decreased vibration sense,
decreased ankle jerks and distal paraesthesiae (Mollman, 1990).
Ototoxicity: Cisplatin commonly causes hearing loss, characterised by
high frequency hearing deficit, tinnitus and vestibular dysfunction
(Maiese et al, 1992).
8.5 Toxicodynamics
Cytotoxic agents such as cisplatin affect a wide variety of cells. The
major toxic effects induced by cisplatin can be classified as
gastrointestinal, renal, audiological and haematological. The
principal target organ for cisplatin toxicity in humans is the kidney.
This is manifested by reduced renal function and deranged serum
electrolytes. Doses of cisplatin sufficient to cause changes in renal
function may not be associated with any histopathological alterations,
although higher doses of the drug may lead to tubular necrosis,
interstitial nephritis and cast formation (Anon, 1982). Cisplatin also
causes nausea, vomiting and diarrhoea, bone marrow hypoplasia, changes
in liver function, ototoxicity and peripheral neuropathy.
8.6 Pharmacodynamics
The mechanism(s) of action of cisplatin are not fully elucidated.
However cisplatin is believed to have properties similar to those of
bifunctional alkylating agents. The cis configuration is necessary
for the cisplatin complex to exert antineoplastic activity. Cisplatin
binds to DNA and inhibits DNA synthesis, the drug produces interstrand
and intrastrand crosslinks in DNA, possibly by binding at areas of
specific base sequences (Reynolds, 1993; Dollery, 1991; Rozencweig et
al, 1977). The relative importance of intrastrand or interstrand DNA
crosslinks, in cisplatin's antineoplastic activity remains to be
clearly determined.
The drug is mainly cell cycle non-specific, though the effects on
crosslinking are most pronounced during the S phase. Recent data
suggest that mitochondrial injury in the proximal tubule is the
primary event in cisplatin nephrotoxicity, this causes inhibition of
ATP-dependent cellular processes including ion transport (Dollery,
1991).
8.7 Kinetics
8.7.1 Absorption by route of exposure
A peak plasma concentration of 5.9 mg/L was reported at the end of a
one hour infusion of 70 mg/m2 of cisplatin. (Baselt and Cravey,
1989). When cisplatin is administered by an intravenous infusion over
6 or 24 hours, plasma concentrations of total platinum peak
immediately following the infusion and increase gradually during the
infusion. Following 6 hour intravenous infusions of 100mg/m2 to
patients with normal renal function, peak total plasma platinum and
non-protein bound plasma platinum concentrations ranged between
2.5-5.3 mg/L and 0.22-0.73 mg/L, respectively (McEvoy, 1995).
Following intra-arterial infusion of cisplatin, local tumour exposure
to the drug is increased as compared with intravenous administration
as evidenced by increased plasma platinum concentrations in local
veins draining the infused region compared with systemic veins and by
increased areas under the curve calculated for local versus systemic
exposure.
Cisplatin is rapidly and well absorbed systemically following
intraperitoneal administration, resulting in 50-100% of the degree of
systemic exposure compared with intravenous administration when
comparable doses are given (McEvoy, 1995).
8.7.2 Distribution by route of exposure
After intravenous administration cisplatin disappears from the plasma
in a biphasic manner. Plasma levels of total platinum show an initial
distribution with a plasma half-life of 25-49 minutes (a) followed by
a second phase with a half-life of 58-73 hours (b) (De Conti et al,
1973). About 90% of the drug is protein bound within 2-4 hours of
administration, and this binding is only partly reversible (Balis et
al, 1983). Cisplatin is concentrated in the kidneys, liver, large and
small intestines. Penetration into the central nervous system appears
to be poor (Rozencweig et al, 1977).
8.7.3 Biological half-life by route of exposure
Although total platinum has a bi-exponential decline with a prolonged
terminal half-life of 58-73 hours, the unbound fraction which has
cytotoxic activity has a much more rapid decline with a half-life of
40-48 minutes (Balis 1983).
8.7.4 Metabolism
The active moiety of cisplatin is the hydrated form of the drug. The
reactions shown are believed to occur in aqueous solutions. It is
believed that the doubly charged diaquo species is responsible for the
drug's antitumour activity. Further metabolism of these species
involves interaction with and binding to cellular components including
nucleic acids and proteins (De Conti et al, 1973).
8.7.5 Elimination by route of exposure
Cisplatin is mainly excreted by glomerular filtration in the urine. Up
to 43% of a dose has been reported to be excreted in urine over 50
days (Reynolds, 1990). Initially cisplatin is excreted unchanged and
later most of the drug is excreted as biotransformation products.
However, excretion is incomplete and platinum may be detected in
tissue for several months after cessation of therapy.
9 MANAGEMENT
9.1 First-aid measures and management procedures
There is no specific antidote, treatment is symptomatic and
supportive. Initially hydration is the most important aspect of
treatment, volumes of 3-4 litres per day have been used in adults,
whilst children have received 3L/m2/day (Haupt et al, 1989), to
reduce the risk of nephrotoxicity. Severe nausea and vomiting may be
managed with antiemetics (e.g. ondansetron, metoclopramide or
buspirone). Patients should be monitored closely for signs and
symptoms of toxicity especially ototoxicity, and changes in cardiac,
liver, renal and neurological function.
9.2 Decontamination
Remove and discard any contaminated clothing, laundering of
non-disposable materials has not been demonstrated to remove cytotoxic
contaminants. Cytotoxic waste may be placed in a thick sealable
polythene bag, then within a second bag and sealed. The bags must then
be labelled and destroyed appropriately.
Treatment for dermal exposure to cisplatin involves washing the
exposed area thoroughly with soap and water. If pain and irritation
persists, treat symptomatically and supportively.
Exposed eyes should be irrigated with copious amounts of water or
saline for at least 15 minutes. The eye should then be stained with
fluorescein. If irritation, pain, swelling, lacrimation or photophobia
persists after 15 minutes of irrigation consult an ophthalmologist.
Cisplatin is not thought to be absorbed through the gastrointestinal
tract, although preliminary reports suggest that this may occur in
rats and mice. In case of ingestion empty the stomach within 2 hours
of ingestion, there is no evidence that activated charcoal will bind
cisplatin.
9.3 General principles
Treatment is symptomatic and supportive. There is no specific
antidote. Patients should be monitored closely for signs and symptoms
of toxicity, especially ototoxicity, cardiac, liver, renal and
neurological function.
Since cisplatin is not available in an oral dosage form, gut
decontamination is not usually required. Initially hydration is the
most important aspect of treatment. Intravenous administration of
fluids (usually normal saline) in volumes of 3-4 litres per day has
been used to reduce the risk of nephrotoxicity. In severe poisoning
the volume of fluid administered may be increased to 5-6 litres daily.
Severe nausea and vomiting may be managed with antiemetics, either
metoclopramide or buspirone. Convulsions may be controlled by
diazepam. If convulsions cannot be controlled or recur, administer
phenytoin or phenobarbitone.
Severe myelosuppression may occur and peripheral blood counts should
be monitored weekly. The lowest counts may be seen at about 2-3 weeks
post-exposure. Monitor patient for bleeding episodes and infection.
Transfusions of packed red cells and platelets may be required if
severe bleeding occurs. If infection occurs, culture the organism and
begin appropriate antimicrobial therapy. Monitor and correct
electrolyte disturbances, including serum creatinine and creatinine
clearance or glomerular filtration rate as appropriate. Renal function
should be closely followed. Monitor the ECG and perform liver function
tests. Sensory potentials, visual evoked potential and brainstem
auditory evoked potentials may provide early evidence of central
nervous system toxicity.
9.4 Life supportive procedures and symptomatic/specific
treatment
The principal target organ for cisplatin toxicity is the kidney,
therefore vigorous rehydration is initially the most important
requirement, following patient stabilisation. Monitor and correct
electrolytes. Monitor audiological, cardiac, liver, and neurological
function.
Management of cisplatin extravasation is based on clinical experience
and published case reports. Cases of extravasation should be prevented
through careful administration of vesicant drugs such as cisplatin.
Check frequently for venous blood return and for signs of redness and
swelling during administration. If extravasation occurs, stop the
infusion immediately and attempt to aspirate some of the extravasated
fluid before withdrawing the needle. Both topical cooling and sodium
thiosulphate have been advocated as possible antidotes after
extravasation of cisplatin. Isotonic sodium thiosulphate (0.17mol/L)
was administered by deep intramuscular injection around a chlomethine
injection site, a vesicant drug, and an ice pack placed on the area
for 12 hours. This provided complete protection from the expected
tissue necrosis (Bertelli, 1995).
9.5 Elimination
Haemodialysis was ineffective in preventing the development of
cisplatin toxicity when started 4 hours post-overdose possibly due to
rapid protein binding (Brivet et al, 1986). It will be indicated if
renal failure occurs.
It has been suggested that removal of plasma proteins by plasma
exchange might be an effective method of reducing the body burden
following overdose (Poisindex, 1995).
9.6 Antidote treatment
There is no specific antidote for cisplatin and treatment is generally
symptomatic and supportive.
9.7 Clinical chemistry/toxicological analysis
9.7.1 Biomedical analysis
Monitor electrolytes, blood urea nitrogen, serum creatinine,
creatinine clearance and peripheral blood counts.
9.7.2 Toxicological analysis
Unlikely to be required.
9.7.3 Other investigations
Monitor the ECG and liver function tests. Sensory potentials, visual
evoked potentials and brainstem auditory evoked potentials may provide
early evidence of central nervous system toxicity.
9.8 Management discussion: alternatives and
controversies
Fosfomycin, a phosphonic acid antibiotic produced from streptomyces
species is being investigated for efficacy in prevention of cisplatin
induced ototoxicity, renal toxicity, and haemopoietic toxicity.
Fosfomycin has been reported in animals and humans to be effective in
inhibition of nephrotoxicity of aminoglycosides when coadministered.
Supplemental treatment with fosfomycin (2 grams twice daily from the
first to the fourth day of each cycle) was shown to reduce cisplatin-
induced nephrotoxicity in one study. Additional studies are needed to
demonstrate efficacy for the use of fosfomycin in cisplatin overdose
(Umeki et al, 1988).
Sodium thiosulphate may protect against cisplatin induced
neurotoxicity. In vitro and in vivo demonstrations have shown
prevention of certain toxic effects of cisplatin by several thiol
containing compounds. Twenty four patients were studied to determine
if sodium thiosulphate injection would permit larger cisplatin doses
to be administered. A fixed dose of 9.9g/m2 of thiosulphate was given
intravenously over three hours concurrently with escalating doses of
cisplatin. Cisplatin was administered over the last two hours of the
thiosulphate infusion. Using this technique, it was possible to
escalate the cisplatin dose to 225mg/m2 before dose limiting
toxicities were encountered. Sodium thiosulphate was also shown to
reduce the side effects of cisplatin to a minimal level without
impairing its antitumour activity in a study of 61 patients (Pfeifle
et al, 1985). Additional studies are needed to determine if sodium
thiosulphate administered after an overdose will prevent cisplatin
nephrotoxicity (Pfeifle et al, 1985).
Supplemental treatment with steroids, methylprednisolone (250mg) or
hydrocortisone (300mg) once a day on the first day of each cycle was
effective in reducing cisplatin-induced nephrotoxicity in one study.
Additional studies are required to demonstrate efficacy for the use of
these steroids in cisplatin overdose (Umeki et al, 1988).
A combination of verapamil (80 mg orally three times daily) and
cimetidine (200 mg orally three times daily plus an additional
intravenous dose of 400 mg on days 1-5, 2 hours before every cisplatin
infusion) beginning one day before the cisplatin dose, was found to be
protective for cisplatin-induced nephrotoxicity. Additional studies
are needed to demonstrate efficacy for the use of verapamil and
cimetidine in cisplatin overdose (Poisindex, 1995).
Cisplatin exerts its antitumour effects through positively charged
electrophilic alkyl groups which prevent or disrupt cell division. It
is these groups, however that are also responsible for the adverse
effects of cisplatin. These adverse effects can be reduced by
providing excess neutrophilic sites such as free sulphydryl groups
through the use of so called chemoprotective agents. However,
provision of excess neutrophilic sites must be selective otherwise
antitumour activity will also be reduced. Chemoprotective agents which
have been investigated include amifostine (WR 2721),
diethyldithiocarbamate (DDTC), ORG 2766 (Gandara et al, 1991;
Schuchter et al, 1992) and glutathione (Bohm et al, 1991).
In phase 1 trials of amifostine in combination with mannitol diuresis.
Transient nephrotoxicity occurred in 9 of 30 (27%) patients treated
with cisplatin 150mg/m2 and in 7% treated with 120mg/m2. Bone
marrow suppression was mild and infrequent. Mild to moderate
neuropathies occurred in 26% of patients on a mean cumulative
cisplatin dose of 725mg/m2 (Glover et al, 1989). Amifostine is now
available from Schering-Plough and is licensed for use in patients
with advanced ovarian cancer to reduce the neuropenia related risk of
infection due to cisplatin or cyclophosphamide therapy. The efficacy
of amifostine in overdose has not been evaluated.
Diethyldithiocarbamate (DDTC) has been used in an investigational
phase 1 clinical trial to demonstrate the feasibility of using DDTC
for renal protection at standard cisplatin doses of 50-120 mg/m2. A
further study reported preliminary observations of plasma platinum and
DDTC pharmacokinetics for high-dose cisplatin (200 mg/m2/cycle). A
dose of 4g/m2 was administered by intravenous infusion over 1.5-3.5
hours beginning 45 minutes after completion of the cisplatin infusion.
Predicted plasma DDTC levels for chemoprotective effect (greater than
400 micromoles) were achieved with this dose and schedule. However the
DDTC infusion resulted in side effects including flushing, chest
discomfort, and anxiety. Additional studies are needed before DDTC can
be recommended for the treatment of cisplatin overdose (Poisindex,
1995).
An ACTH (4-9) analogue, ORG 2766, is being investigated as a means of
preventing cisplatin neurotoxicity. One study found that 0.25mg (low
dose) or 1mg/m2 (high dose) of ORG 2766 administered subcutaneously
before and after treatment, with cisplatin and cyclophosphamide could
attenuate or prevent cisplatin neuropathy (van der Hoop et al, 1990).
Further studies are required before this treatment can be recommended
in humans following overdose.
10 LABORATORY INVESTIGATIONS
10.1 Sample collection
Flameless atomic absorption spectrometry has been used to determine
free or total platinum in plasma. (Baselt and Cravey 1989). Blood
samples may be collected in heparinized or acid citrate dextrose
tubes, spun in a clinical centrifuge within 10 minutes of collection
and immediately separated as plasma samples for analysis (Chu et al,
1993).
10.2 Transport of laboratory samples and specimens
10.3 Interpretation of toxicological analyses
10.4 Biomedical investigations and their interpretation
Peripheral blood counts should be monitored weekly, the lowest counts
may be seen at about 2-3 weeks post-exposure. Monitor and correct
electrolytes including serum creatinine and creatinine clearance, as
appropriate. Liver function tests should be performed regularly to
reduce the risk of hepatotoxicity.
11 ILLUSTRATIVE CASES
11.1 Case reports from the literature
1) A 41 year old female patient was administered a double dose of
cisplatin (200mg/m2) on the 5th day of her first course of
polychemotherapy for treatment of stage III primary ovarian carcinoma.
Other treatment included doxorubicin (25mg/m2) and teniposide
(35mg/m2) on day 1, cyclophosphamide (200mg/m2) and 5-fluorouracil
(350mg/m2) on days 2-4. On day 5 cisplatin 100 mg/m2 was to be
administered, however two doses were inadvertently administered.
Nausea and vomiting was reported one hour after the second dose of
100mg/m2, treatment with intravenous hydration of 25% mannitol and 5%
dextrose was initiated immediately. The patient complained of
headache, a metallic taste, nausea and thirst. Haemodialysis was begun
four hours after the end of the second dose cisplatin. Five days post
intoxication metabolic acidosis, acute renal failure, and febrile bone
marrow aplasia was reported. Treatment consisted of antibiotics,
haemodialysis and transfusions. Bone marrow depression and acute renal
failure resolved, a second course of chemotherapy two months later
with cisplatin 50mg/m2 produced myelosuppression without renal
failure (Brivet et al, 1986).
2) A 36 year old male with testicular choriocarcinoma developed
oliguric renal failure, febrile myelosuppression, decreased hearing,
thick speech, impairment of taste, and numbness of the hands and feet
one week after a cisplatin overdose. Rather than receiving
40mg/m2/day divided into three equal eight hour infusions, the
patient received a continuous infusion of 40 mg/m2 every eight hours
for 4 days, a total dose of 480 mg/m2. The patient required
haemodialysis for 1 month until his serum creatinine fell below 8
mg/100ml. On follow up eighteen months later dysarthria, taste
disturbance and left hand weakness had resolved, serum creatinine had
stabilized at 3.5mg/100ml and his creatinine clearance was 26
ml/minute, however he still required hearing aids (Schiller et al,
1989).
3) A 6 month old infant with a localized, unresectable embryonal
rhabdomyosarcoma of the shoulder received an overdose of cisplatin,
90mg/m2 of cisplatin daily for 5 days in combination with standard
doses of VP-16 (100mg/m2 for 5 days). The cisplatin was diluted in
250ml/m2 of 3% hypertonic saline and administered as a one hour
infusion with vigorous hydration of 3L/m2/day of normal saline.
Vomiting began on day 2 and continued for 7 days, diarrhoea was also
reported, total parenteral nutrition was required for 28 days. Severe
haematological toxicity occurred, white blood cells dropped to 800/mmc
in 10 days with PMNs below 500/mmc from the 5th to the 17th day from
the end of the cycle. Pyrexia (39°C) developed on day 10 and resolved
24 hours later following antimicrobial therapy. A nadir in platelet
count of 5000/mmc was observed on day 13. Treatment involved
transfusion of four units of platelets and haemoglobin was maintained
over 10g/L with three transfusions of packed red cells. Renal function
was monitored daily, no elevation of serum creatinine, BUN or uric
acid was observed, but by the 8th day after treatment, moderate
hyperchloraemic acidosis developed as a result of severe impairment in
the tubular function with urinary bicarbonate losses up to 10 times
the normal values for the patient's age. The impairment continued for
three weeks and then gradually resolved completely. Daily EEGs and
peripheral nerve function normal (Haupt et al, 1989).
11.2 Internally extracted data on cases
No data available.
12 ADDITIONAL INFORMATION
12.1 Specific preventive measures
None.
12.2 Other
None.
Authors
Robie Kamanyire
National Poisons Information Service (London Centre)
Medical Toxicology Unit
Guy's & St Thomas' Hospital Trust
Avonley Road
London
SE14 5ER
UK
This monograph was produced by the staff of the London Centre of the
National Poisons Information Service in the United Kingdom. The work
was commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review was undertaken by the Directors of the UK National Poisons
Information Service.
June 1995
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