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    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 27C. 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).

    FIGURE

    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 (39C) 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

    REFERENCES

    Anon. (1982)
    Cisplatin.
    Lancet 1:374-375

    Balis FM, Holcenberg JS, Bleyer WA. (1983)
    Clinical pharmacokinetics of widely used anticancer drugs.
    Clin Pharmacokin 8 (3): 202-32

    Baselt RC and Cravey RH. 1989
    Disposition of toxic drugs and chemicals in man 3rd ed.
    Year Book Medical Publishers

    Bennett WM, Pastore L and Houghton DC. (1980)
    Fatal pulmonary toxicity in cis-platin induced renal failure.
    Cancer Treat Rep 64:921-924

    Bertelli G. (1995)
    Prevention and management of extravasation of cytotoxic drugs.
    Drug Safety 12(4):245-255

    Bohm S, Spatti GB, Di Re F, Oriana S, Pilotti S, Tedeschi M, Tognella
    S and Zunino F. (1991)
    A feasibility study of cisplatin administration with low volume
    hydration and glutathione protection in the treatment of ovarian
    carcinoma.
    Anticancer Res 11: 1613-1616

    Briggs GG, Freeman RK and Yaffe SJ. (1994)
    Drugs in Pregnancy and Lactation 4th ed.
    Williams and Wilkins

    Brivet F, Pavlovitch J-M, Gouyette A, Cerrina M-L, Tcherina G and
    Dormont J. (1986)
    Inefficiency of early prophylactic hemodialysis in cis-platinum
    overdose.
    Cancer Chemother Pharmacol 18:183-184

    Chu G, Mantin R, Yu-Min S, Baskett G and Sussman H. (1993)
    Massive cisplatin overdose by accidental substitution for carboplatin.
    Toxicity and management.
    Cancer 72 (12):3707-3714

    De Conti RC, Toftness BR, Lange RC and Cresey WA. (1973)
    Clincial and pharmacological studies with cis-diamminedichloroplatin
    (II).
    Cancer Res 33:1310-1315

    De Vries EGE, van der Zee AGJ, Uges DRA, Sleijfer DT. (1989)
    Excretion of platinum into breast milk (letter).
    Lancet 1:497

    Doll DC, List AF, Greco FA, Hainsworth JD, Hande KR, Johnson DH.
    (1986)
    Acute vascular events after cisplatin based combination chemotherapy
    for germ-cell tumours of the testis.
    Ann Intern Med 105: 48-51

    Dollery C (ed). (1991)
    Therapeutic drugs.
    Churchill Livingstone

    Dorr RT and Fritz WL. (1980)
    Cancer Therapy Handbook.
    Elsevier

    El-Sharkawi AM, Morgan WD, Cobbold S, Jaib MBM, Evans CJ, Somerville
    LJ, Chettle DR, Scott MC. (1986)
    Unexpected mobilisation of lead during cisplatin chemotherapy.
    Lancet 2:249-250

    Fassio T, Cannobbio L, Gasparini G et al. (1986)
    Paroxysmal supraventricular tachycardia during treatment with
    cisplatin and etoposide combination.
    Oncology 43:219-220

    Fassoulaki A and Pavlou H. (1989)
    Overdosage intoxication with cisplatin-a cause of acute respiratory
    failure.
    J R Soc Med 82:689

    Gandara DR, Perez EA, Wiebe V and De Gregorio MW. (1991)
    Cisplatin chemoprotection and rescue: pharmacologic modulation of
    toxicity.
    Sem Oncol 18 (1):49-55

    Glover D, Grabelsky S, Fox K, Weiler C, Cannon L and Glick J. (1989)
    Clincial trials of WR 2721 and cis-platinum.
    Int J Radiation Oncol Biol Phys 16:1201-1204

    Gonzalez-Vitale JC, Hayes DM, Cvitkovic E and Sternberg SS. (1978)
    Acute renal failure after cis-dichlorodiammineplatinum (II) and
    gentamicin-cephalothin therapies.
    Cancer Treat Rep 62:693

    Grant WM. (1986)
    Toxicology of the eye 3rd ed.
    Charles C Thomas

    Haupt R, Perin G, Dallorso S, Garre M-L, and Sobrero A. (1989)
    Very high dose cisplatinum (450mg/m2) in an infant with
    rhabdomyosarcoma.
    Anticancer Res 9:427-428

    Howell SB, Pfeifle CL, Wung WZ et al. (1982)
    Intraperitoneal cisplatin with systemic thiosulfate protection.
    Ann Intern Med 97:845-851

    Jacobs AJ, Marchevsky A, Gordon RE, Deppe G and Cohen J. (1980)
    Oat cell carcinoma of the uterine cervix in a pregnant woman treated
    with cis-diamminedichloroplatinum.
    Gynecol Oncol 9:405-410

    Kattah JC, Potolicchio SJ, Kotz HL, Kolsky MP and Thomas D. (1986)
    Cortical blindness and occipital lobe seizures induced by
    cis-platinum.
    Neuro-ophthalmology 7(2):99-104

    Khan A, Hill JM, Grater W, Loeb E, MacLellan and Hill N. (1975)
    Atopic hypersensitivity to cis-Dichlorodiammineplatinum (II) and other
    platinum complexes.
    Cancer Res 35:2766-2770

    Kumar L and Dua H. (1987)
    Cis-platin induced anaemia (letter).
    N Z Med J 100:81.

    Legha SS and Dimery IW. (1985)
    High-dose cisplatin administration without hypertonic saline.
    Observation of disabling neurotoxicity.
    J Clin Oncol 3:1373-1378

    Maiese K, Walker RW, Gargan R and Victor JD. (1992)
    Intra-arterial Cisplatin-associated optic and otic toxicity.
    Arch Neurol 49:83-86

    McEvoy GK. (1995)
    AHFS Drug Information.
    American Society of Health-System Pharmacists

    Mollman JE. (1990)
    Cisplatin neurotoxicity.
    N Engl J Med 322 (2):126-127

    NIOSH. (1995)
    Cisplatin, RTECS-TP25000
    C2 (95-2) Expires 09/95

    Pfeifle CE, Howell SB, Felthouse RD, Woliver TBS, Andrews PA, Markman
    M and Murphy MP. (1985)
    High-dose Cisplatin with sodium thiosulfate protection.
    J Clin Oncol 3:237-244

    Poisindex editorial staff. (1995)
    Cisplatin
    Poisindex vol 85, expires 9/30/95
    Micromedex Inc

    Raffles A, Williams J, Costelve K and Clark P. (1989)
    Transplacental effects of maternal cancer chemotherapy: case report.
    Br J Obstet Gynaecol 96:1099-1100

    Reynolds JEF (ed). (1993)
    Martindale: The Extra Pharmacopoeia 30th ed.
    The Pharmaceutical Press

    Rozencweig M, Von Hoff DD, Slavik M, Muggia FM. (1977)
    Cis-diamminedichloroplatinum (II): A new anticancer drug.
    Ann Intern Med 86:803-812

    Schaeppi U, Heyman IA, Fleischman RW, Rosenkrantz H, Ilievski V,
    Phelan R, Cooney DA, Davis RD. (1973)
    cis-Dichlorodiammineplatinum (II) (NSC-119 875): Preclinical
    toxicologic evaluation of intravenous injection in Dogs, Monkeys and
    Mice.
    Toxicol App Pharmacol 25:230-241

    Schiller JH, Rozental J, Tutsch KD and Trump DL. (1989)
    Inadvertent administration of 480mg/m2 of cisplatin.
    Am J Med 86:624-625

    Schuchter LM, Luginbuhl WE and Meropol NJ. (1992)
    The current status of toxicity protectants in cancer therapy.
    Sem Oncol 19 (6):742-751

    Siddik ZH, Boxall FE, Goddard PM, Bernard CFJ and Herrap KR. (1984)
    Antitumour pharmacokinetic and toxicity studies with orally
    administered cisplatin CBOCA and CHIP.
    Proceed Am Acad Cancer Res 25:469

    Stuart-Harris R, Ponder BAJ, Wrigley PFM. (1980)
    Tetany associated with cisplatin.
    Lancet 2:1303.

    Sylvester RK, Lewis FB, Caldwell KC, Lobell M, Perri R and Sawchuk RA.
    (1984)
    Impaired phenytoin availability secondary to cisplatinum, vinblastine
    and bleomycin.
    Ther Drug Monit 6:302-305

    Umeki S, Watanabe M, Yagi S and Soejima R. (1988)
    Supplemental fosfomycin and/or steroids that reduce cisplatin-induced
    nephrotoxicity.
    Am J Med Sci 295 (1):6-10

    van der Hoop RG, Vecht CJ, van der Burg ML, Elderso A, Boogerd W,
    Heimans JJ, Vries EP, van Houwelingen JC, Jennekens FGI, Gispen WH and
    Neijt JP. (1990)
    Prevention of cisplatin neurotoxicity with an ACTH(4-9) analogue in
    patients with ovarian cancer.
    N Engl J Med 322 (2):89-94

    Von Hoff DD, Schilsky R, Reichert CM, Reddick RL, Rozencweig M, Young
    RC and Muggia FM. (1979)
    Toxic effects of cis-Dichlorodiammineplatinum (II) in man.
    Cancer Treat Rep 63:15271531

    Von Hoff DD, Slavik M, Muggia FM. (1976)
    Allergic reactions to cisplatinum.
    Lancet 1:90

    Yee GC, Crom WR, Champion JE, Brodeur GM and Evans WE. (1983)
    Cisplatin induced changes in bleomycin elimination.
    Cancer Treat Rep 67:587-9