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Cisplatin

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification Numbers
      1.4.1 CAS
      1.4.2 Other Numbers
   1.5 Brand Names, Trade Names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
2. SUMMARY
   2.1 Main Risks and Target Organs
   2.2 Summary of Clinical Effects
   2.3 Diagnosis
   2.4 First aid measures and management practices
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the Substance
   3.2 Chemical Structure
   3.3 Physical Properties
      3.3.1 Properties of the Substance
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.2 Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other Characteristics
      3.4.1 Shelf-Life of the Substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage Conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic Doses
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of Action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human Data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Animal Data
      7.2.3 In-vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main Adverse Effects
8. PHARMACOLOGICAL, TOXICOLOGICAL AND OTHER ANALYSES
   8.1 Sample
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological Analytical Methods
      8.2.1 Tests for active ingredient
      8.2.2 Tests for biological sample
   8.3 Other Laboratory analyses
      8.3.1 Biochemical Investigations
         8.3.1.1 Blood
         8.3.1.2 Urine
         8.3.1.3 Other
      8.3.2 Arterial Blood Gas Analysis
      8.3.3 Haematological or Haemostasiological Investigations
      8.3.4 Other Relevant Biomedical Analyses
   8.4 Interpretation
9. CLINICAL EFFECTS
   9.1 Acute Poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin Exposure
      9.1.4 Eye Contact
      9.1.5 Parenteral Exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin data
      9.2.4 Eye Contact
      9.2.5 Parenteral Exposure
      9.2.6 Other
   9.3 Course, prognosis and cause of death
   9.4 Systemic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral Nervous System
         9.4.3.3 Autonomic Nervous System
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and Reproductive Systems
      9.4.8 Dermatological
      9.4.9 Eye, Ear, Nose, Throat: Local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid Base disturbances
         9.4.12.2 Fluid and Electrolyte Disturbances
         9.4.12.3 Other
      9.4.13 Allergic Reactions
      9.4.14 Other Clinical Effects
      9.4.15 Special risks
10. MANAGEMENT
   10.1 General Principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample Collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other Investigations
   10.3 Life Supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from the Literature
   11.2 Internally extracted data on cases
   11.3 Internal Cases
12. ADDITIONAL INFORMATION
   12.1 Availability of Antidotes
   12.2 Specific Preventative Measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S), COMPLETE ADDRESS(ES)
    1. NAME

       1.1 Substance

           Cisplatin  (INN)

           (WHO,1992)
             
       1.2 Group

           ATC Classification Index

           Antineoplastic and immunomodulating agents (L)/
           Other Cytostatics (L01XA).

           (WHO, 1992)

       1.3 Synonyms

           CACP
           CDDP
           Cisplatino (Spanish)
           CPDC
           CPDD
           Cis-Diamminedichloro platinum (II)
           Cis-Dichlorodiammine platinum (II)
           Cis-platin
           Cis-platinous diammine dichloride
           Cis-platinum
           Cis-platinum II
           Cis-platinum II Diamine dichloride
           Cis PT II
           DDP
           Neoplatin
           NSC-119875
           Peyrone's Salt
           Peyrone's Chloride
           Platinol
           Platinum diamminodichloride
           
       1.4 Identification Numbers

           1.4.1 CAS

                 15663-27-1

           1.4.2 Other Numbers

                  RTECS

                 TP 2450000

                  Laboratory Code

                 NSC 119875


    
                  Wiswesser Line Notation

                 Z&2 PT-G2

       1.5 Brand Names, Trade Names

           Cisplatyl, Cytoplatino, Neoplatin, Placis, Platiblastin, 
           Platinex, Platinol, Platistil, Platistin, Platosin. 
           
           (Reynolds, 1989)
           
           Australia
           
           Cisplatin (David Bull)
           Platamine (Farmitalia)
           Platinol  (Bristol)
           
           (Thomas, 1991; David Bull, 1992)

       1.6 Manufacturers, Importers

           David Bull: Australia
           Bull: UK
           Bellon: France
           Rhne Poulenc: Sweden, Italy
           Bristol Italiana Sud: Italy
           Bristol-Meyers: Spain, Australia, Denmark, Luxembourg
           Bristol-Meyer Oncology: USA
           Bristol-Meyers Pharmaceuticals: UK
           Bristol: Germany, Belgium, Canada, Switzerland, Norway, South
                        Africa, Sweden
           Wusserman: Spain
           Farmitalia Carlo Erba: South Africa, Sweden, UK
           Farmitalia: Germany, Spain, Denmark, Norway
           Nordic: UK
           Lederle: UK
           
           (Reynolds 1989)

       1.7 Presentation, Formulation

           Australia
           
            Cisplatin
           
           Vials containing 10 mg, 25 mg, 50 mg of cisplatin as a 
           lyophilised powder for reconstitution in packs of 1 and 10 
           vials.
           
           Cisplatin Solution
           
           Vials containing cisplatin as a solution in a concentration 
           of 1 mg/ml: 10 mg in 10 ml vial, 50 mg in 50 ml vial, 100 mg 
           in 100 ml vial.
           
           Platamine (Farmitalia)
           
           Vials containing cisplatin in lyophilised powder for 
           reconstitution: 10 mg in 20 ml vials, 25 mg in 50 ml vials 
           and 50 mg in 100 ml vials in packs of 1 vial.
           
           Platinol (Bristol)
           
           Vials containing cisplatin as a lyophilised powder for 
           reconstitution: 10 mg in 20 ml vials and 50 mg in 100 ml 
           vials
           
           Vials containing cisplatin as a solution in a concentration 
           of 0.5 mg/ml; 10 mg in 20 ml vial, 25 mg in 50 ml vial and 50 
           mg in 100 ml vial.
           
           (Thomas, 1991;David Bull, 1992)

    2. SUMMARY

       2.1 Main Risks and Target Organs

           The main risks experienced during cisplatin therapy and 
           overdosage include nephrotoxicity, electrolyte disturbances, 
           myelosuppression, neurotoxicity, anaphylactic reactions, 
           ototoxicity. Nausea and vomiting can be severe.
           
           Rarer risks include cardiovascular effects, ocular effects, 
           and hepatic effects.
           
           Most effects of overdosage are not usually seen immediately, 
           but occur several days to months after the event.
           
           The causes of death from an overdose from cisplatin include 
           myelosuppression, renal failure and tetany. 
     
       2.2 Summary of Clinical Effects

           Renal toxicity is cumulative and seen usually after several
           courses of cisplatin or after overdose (see Section 11).
           
           Disturbances in electrolytes can be a long term manifestation 
           due to the cisplatin induced renal tubular dysfunction.  
           Hypomagnesaemia, hypocalcaemia and hypokalaemia are commonly 
           seen in cisplatin induced renal toxicity and can persist for 
           months after termination of therapy.
           
           Haematological effects of cisplatin (myelosuppression and 
           anaemia) are cumulative and in overdosage the haematopoietic 
           system must be supported to prevent complications of 
           infection.
           
           Cisplatin induces marked nausea and vomiting in almost all 
           patients.
           
           Anaphylactoid reactions have occurred during normal therapy 
           with cisplatin and must be treated vigorously. Cisplatin 
           causes electrolyte disturbances which are a direct result of 
           cisplatin induced renal tubular dysfunction.  Cisplatin 
           causes marked excretion of calcium, magnesium and potassium 
           and to a lesser extent zinc, copper and amino acids. These 
           disturbances must be corrected to prevent complications. 

       2.3 Diagnosis

           Clinical features
           
           Renal toxicity is manifested by an increase in serum 
           creatinine, BUN, serum uric acid and/or a decrease in 
           creatinine clearance and glomerular filtration rate.
           
           The renal impairment is a direct result of cisplatin induced 
           renal tubular damage leading ultimately to renal failure.
           
                   Disturbances have been seen in serum electrolytes 
           due principally to cisplatin induced renal tubular 
           dysfunction.  Patients subsequently develop hypomagnesaemia, 
           hypocalcaemia and hypokalaemia and to a lesser extent 
           hypophosphatemia and hyponatremia.
           
                   Cisplatin produces marked nausea and vomiting in
           almost all patients to the extent that some patients 
           experience anticipatory nausea and vomiting.  Diarrhoea has 
           also occurred but with less frequency than nausea and 
           vomiting.
           
                   Ototoxicity develops in various degrees on cisplatin
           therapy.  In larger and prolonged dosing with cisplatin the 
           ototoxicity can be irreversible.
           
                   Myelosuppression is a common problem seen as
           leucopenia, thrombocytopenia and anaemia and if severe enough 
           can cause the death of the patient.
           
                   Myelosuppression can be cumulative.
           
                   Anaphylactoid reactions can occur when cisplatin is 
           given.
           
                   Cardiovascular effects are rare but include
           bradycardia, left bundle branch block and congestive heart 
           failure.
           
                   Hepatic enzyme concentrations in the sera become
           elevated including AST (SGOT) and ALT (SGPT).
           
           Laboratory analyses
           
           Serum electrolyte concentration should be ascertained 
           throughout treatment including magnesium, potassium, calcium 

           as well as other renal function tests.  These values give an 
           indication of the renal damage caused by cisplatin.
           
           Peripheral blood counts should also be monitored as these 
           give an indication of the degree of myelosuppression and 
           anaemia.
           
           Liver function tests should also be performed regularly.  
           
           Visual and auditory tests should be performed throughout as 
           some of the effects are reversible and it gives an indication 
           of the severity of toxicity.
           
           ECG and other cardiac monitoring tests should be employed to 
           recognize electrolyte and cardiac disturbances.
           
           (Gilman et al., 1985; NDIS, 1985; McEvoy, 1992; David Bull, 
           1992; Fassoulaki & Pavlov, 1989; Reynolds, 1989; Schiller et 
           al., 1989) 

       2.4 First aid measures and management practices

           Treatment is supportive and symptomatic.
           
           Patients should be monitored for 3 to 4 weeks post 
           administration to determine the severity of toxicity as 
           effects are delayed.
           
           There is no specific antidote to use in cisplatin toxicity.
           
           Treatment must involve hydration with 3 to 6 litres of 
           intravenous fluids per day together with intravenous 
           mannitol, both of which increase urinary volume and output 
           and decrease the effective urinary concentration of platinum.
           
           Decontaminate skin or eyes if route of exposure to cisplatin 
           was in this manner.  Copious amounts of water (or appropriate 
           irrigation fluid) should be used.
           
           Emesis, gastric lavage, charcoal therapy are not appropriate 
           (but if an overdose occurred orally, these measures would be 
           used appropriately) as cisplatin is not usually administered 
           in this manner. The overdoses to date in the literature have 
           been administered intravenously.
           
           (Schiller et al., 1989; Fassoulaki & Pavlov, 1989; McEvoy, 
           1992; NDIS, 1985) 

    3. PHYSICO-CHEMICAL PROPERTIES

       3.1 Origin of the Substance

           Synthetic

       3.2 Chemical Structure

           Structural formula
           
           
           Cl             NH3
           
           
                      Pt
           
           
               Cl              NH3
           
           
           Molecular Weight
           
           300.05
           
           Molecular Formula
           
           Cl2H6N2Pt or (NH3)2PtCl2
           
           Structural name(s)
           
           cis - Diamminedichloroplatinum

       3.3 Physical Properties

           3.3.1 Properties of the Substance

                 3.3.1.1 Colour
                                                        
                         Deep yellow solid. 

                 3.3.1.2 State/Form

                         Solid.

                 3.3.1.2 Description

                         Decomposes at 270 C
                         
                         Soluble in water, 0.253 g/100 g at 25 C, 
                         1 mg/mL in 0.9% sodium chloride
                         
                         Slowly changes from the cis to the trans form 
                         in aqueous solution.
                         
                         Soluble in dimethylformamide.
                         
                         Insoluble in most common solvents.
                         
                         (McEvoy, 1992; Budavari, 1989)
                         
           3.3.2 Properties of the locally available formulation(s) 

                 To be completed by the Centre.

       3.4 Other Characteristics

           3.4.1 Shelf-Life of the Substance

                 Cisplatin lyophilised powder - unopened vials of the 
                 dry powder must be kept under refrigeration (2 to 5C) 
                 and are stable for 25 months from date of manufacture. 
                 
                 (David Bull, 1992)

           3.4.2 Shelf-life of the locally available formulation 

                 To be completed by the centre, according to local data, 
                 e.g. 
                 
                 Cisplatin solution (Platinol-Bristol) - unopened vials 
                 of solution must be kept at temperatures above freezing 
                 and below 25C and are stable for 24 months from the 
                 date of manufacture. (Australia)
                 
                 Cisplatin Solution (DBL) - unopened vials of solution 
                 must be kept at temperatures between 15 and 25C and 
                 are stable for 24 months from date of manufacture. 
                 (Australia)
                 
                 (David Bull, 1992, Thomas, 1991).

           3.4.3 Storage Conditions

                 Store each product as recommended by the manufacturer. 
                 
                 Cisplatin lyophilised powder - Store under 
                 refrigeration (2-8C) and protect from light.
                 
                 Cisplatin solution (Platinol-Bristol) - Store above 
                 freezing and below 25C.  Protect from light.
                 
                 Cisplatin Solution (DBL) - Store between 15 and 25C, 
                 and protect from light.
                 
                 The stability of reconstituted solutions:
                 
                       22 hrs-Cisplatin (David Bull)
                       24 hrs-Platinamine (Farmitalia)
                       20 hrs-Platinol (Bristol)
                 
                 The reconstituted solution should be stored at room 
                 temperature and protected from light.  (If stored at 
                 refrigerator temperatures a crystalline precipitate 
                 forms).
                 
                 Aluminium-containing intravenous sets, needles, 
                 catheters and syringes etc should be avoided due to an 
                 interaction resulting in a precipitation of platinum.
                 
                 (Thomas, 1991, David Bull, 1992)

           3.4.4 Bioavailability

                 Lyophilised powder dissolves readily in intravenous 
                 fluids containing chloride ions (0.9% sodium chloride, 
                 5% dextrose with 0.18% sodium chloride). 
             
           3.4.5 Specific properties and composition

                 Commercially available cisplatin powder for injection 
                 is a lyophilised powder and contains sodium chloride, 
                 mannitol and hydrochloric acid (to adjust the pH).
                 
                 Solutions containing 1 mg/mL of cisplatin are clear and 
                 colourless and have a pH of 3.5 to 5.5.
                 
                 Commercially available cisplatin injection is a clear 
                 and colourless solution and contains sodium chloride, 
                 hydrochloric acid and/or sodium hydroxide to adjust the 
                 pH.  The pH is in the range 3.7 to 6, an osmolality of 
                 about 285 to 286 Osm/kg and contains 0.9% sodium 
                 chloride.  Depending on the manufacturer, the injection 
                 does or does not contain mannitol. 

    4. USES

       4.1 Indications

           Cisplatin is indicated for the following conditions:
           
           - single agent for the treatment of transitional cell bladder 
           carcinoma that is no longer amenable to local treatment such 
           as surgery and/or radiation therapy.
           
           - locally advanced or metastatic transitional cell carcinoma 
           involving the renal pelvis, ureter, bladder and/or 
           urethra.
           
           - in combination with radiation treatment to treat bilharzial 
           bladder cancer and together with doxorubicin and 
           cyclophosphamide to treat locally advanced bladder 
           cancer.
           
           - the palliative treatment of recurrent or metastatic 
           squamous cell carcinomas of the head or neck.
           
           - treatment of lung cancer, principally as a component of 
           various chemotherapeutic regimens in the treatment of non-
           small cell lung carcinomas.  It is often combined with other 
           agents such as etoposide, vinblastine or vindesine to obtain

           a better response rate in lung cancer.  Its use alone has 
           some value but in combination the results are more 
           rewarding.**
           
           - in the palliative treatment of recurrent or advanced 
           squamous cell carcinoma of the cervix and metastatic 
           testicular carcinoma.
           
           - other types of carcinomas in which cisplatin has been tried 
           included the following: osteogenic sarcoma, neuroblastoma and 
           recurrent brain tumours in children, advanced oesophageal 
           carcinoma and advanced prostatic carcinoma.
           
           ** In combination with agents such as bleomycin, 
           methotrexate, vincristine or vinblastine, fluorouracil in 
           various regimes (all together or singularly depending on the 
           protocol and the carcinoma type).  Combinations of these 
           agents have been reported to have a better response rate than 
           if cisplatin were used alone.

       4.2 Therapeutic Doses

           Adults
           
           Dosage of cisplatin depends on the clinical, renal, 
           haematological and otic response and tolerance of the patient 
           in order to obtain optimal responses.
           
           Dosage of cisplatin depends also on the carcinoma being 
           treated, the combination with other cancer chemotherapy 
           agents and/or radiation and published protocol chosen for 
           that carcinoma.
           
           Cisplatin is administered by the intravenous route.  At the 
           usual dosage, courses of cisplatin therapy should not be 
           given more frequently that once every 3 to 4 weeks.  A repeat 
           course of cisplatin should not be administered until the 
           patient's renal, haematological and otic functions are within 
           acceptable limits and precautions should always be taken to 
           treat any anaphylactic reactions that may occur.
           
           Cisplatin should only be used by physicians experienced in 
           administration of cytotoxic agents and in the management of 
           potential side effects in particular nephrotoxicity and 
           myelosuppression.
           
           Some dosage schemes are as follows:
           
           Single Agent Therapy
           
                  2 to 3 mg/kg every 3 to 4 weeks
                  20 mg/m2/day for 5 days every 3 to 4 weeks
                  100 mg-120 mg/m2 every 3 to 4 weeks
                  80 mg/m2 (24 hour infusion) every 3 to 4 weeks
           
           Some examples of disease states protocols are as follows:
           
           Testicular Neoplasms
           
           For remission induction (in combination with bleomycin and 
           vinblastine): 
           
                 20 mg/m2 intravenously daily for 5 consecutive days 
                 every 3 weeks for three to four courses; or 120 mg/m2 
                 every 3 to 4 weeks for three courses. 
           
           Ovarian Neoplasms
           
           Dosage of cisplatin in combination chemotherapy regimens 
           (e.g. Doxorubicin): 50 mg/m2 once every 3 to 4 weeks.
           
           As a single agent: 100 mg/m2 intravenously once every four 
           weeks (doses of 30 to 120 mg/m2 intravenously once every 3 to 
           4 weeks have also been used).
           
           Bladder Cancer
           
           Cisplatin 50 to 70 mg/m2 intravenously once every 3 to 4 
           weeks.  The dose depends on prior chemotherapy and/or 
           radiation treatment. 
           
           Head and Neck Cancer
           
            Cisplatin alone
           
                  80 to 120 mg/m2 intravenously once every 3 weeks; or 
                  50 mg/m2 intravenously on the first and eighth days
                  every four weeks.
           
            Combined therapy
           
                  80 to 120 mg/m2 - the frequency is determined by
                  the protocol.
           
           Cervical Carcinoma
           
           Dosages of 50 mg or 100 mg/m2 intravenously once every three 
           weeks have been used (the lower dose is just as effective as 
           the higher dose with less side effects). 
           
           The dose to treat cervical carcinoma therefore have yet to be 
           established. 
           
           Non-small Cell Lung Carcinoma
           
            Cisplatin alone
           
                  75 to 120 mg/m2 intravenously once every 3 to 6 weeks.
                  Also 50 mg/m2 intravenously on days 1 and 8 of a four-
                  week course.
           
            In combination with other agents
           
                  40 mg-120 mg/m2 intravenously every 3 to 6 weeks has 
                  been employed (e.g. 120 mg/m2 on days 1 and 28 or 29, 
                  then once every 6 weeks).
           
           All appear effective.
           
           Intra-Arterial Dosage
           
           When cisplatin is given intra-arterially a dose of 75 to 150 
           mg/m2 2 to 5 weekly for at least 1 to 4 courses is used.  
           This is used in regionally confined malignancies, e.g. 
           advanced bladder cancer, malignant melanoma and osteogenic 
           sarcomas.
           
           Intraperitoneal Dosage
           
           The management of intraperitoneal tumours, where the tumour 
           is confined to the peritoneal cavity and/or associated with 
           malignant ascites, includes the use of cisplatin.
           
            Dosage
           
           60 to 90 mg/m2 intraperitoneally with intravenous sodium 
           thiosulphate (e.g. 7.5 g/m2 loading dose followed by 
           2.13 g/m2 /hour for 12 hours). 
           
           Doses of up to 270 mg/m2 intraperitoneally have been used
           with or without sodium thiosulphate.
           
           Both these dosage regimens have been repeated every 3 weeks.
           
           Combination Therapy
           
           Cisplatin is commonly used in combination therapy with the
           following cytotoxic agents:
           
           a)    Testicular Cancer: Vinblastine, Bleomycin, 
                 Actinomycin D
           
           b)    Ovarian Cancer: Cyclophosphamide, Doxorubicin,
                 Hexamethylmelamine, 5-Fluorouracil
           
           c)    Head and Neck Cancer:  Bleomycin, Methotrexate.
           
           Pretreatment hydration with 2 litres of 5% Glucose and 1/2 to 
           1/3 normal saline infused over a 2 to 4 hour period prior to 
           cisplatin therapy is recommended. 
           
           Post treatment hydration and urinary output must be maintained
           during the following 24 hours.
           
           (McEvoy, 1992; Gilman et al., 1985; NDIS, 1985)
           
           Children
           
           Paediatric dosage of cisplatin has not been fully established.
           
            Osteogenic sarcoma or neuroblastoma
           
           Cisplatin been used in the treatment of the above  in doses 
           of 90 mg/m2 intravenously once every 3 weeks or 30 mg/m2 
           intravenously once weekly. 
           
            Recurrent brain tumours
           
           Doses of 60 mg/m2 intravenously daily for two consecutive 
           days every 3 to 4 weeks have been used. 
           
            Renal Impairment
           
           It has not been clearly determined whether dosage should
           routinely be reduced in patients with renal impairment.
           
           Some dosages that have been tried are 75% of the usual dose 
           when creatinine clearances of  10 to 50 mL/min are present.  
           Similarly, creatinine clearances of less than 10 mL/min 
           should be 50% of usual dose. 
           
           There is an argument that by reducing doses this might result 
           in suboptimal therapy.
           
           (McEvoy, 1992; Gilman et al., 1985; NDIS, 1985)

       4.3 Contraindications

           Absolute
           
           A history of hypersensitivity to cisplatin or other platinum 
           containing compounds. 
           
           Relative
           
           Cumulative and dose related renal insufficiency is the major 
           dose limiting toxicity of cisplatin.  Incidence and severity 
           increases with total dose and duration of treatment.
           
            Myelosuppression
           
           During treatment, the platelet and leucocyte circulating 
           concentrations are at their lowest between days 18 and 32 
           (range 7.3 to 45) and most patients start recovery by day 39 
           (range 13 to 62).
           
           Leucopenia and thrombocytopenia are more pronounced after
           using doses of greater than 50 mg/m2.
           
           Subsequent doses of cisplatin should not be commenced until 
           the platelet count is greater than 100,000/cubic mm and white 
           cells are greater than 4000/cubic mm.
           
            Nausea and vomiting
           
           Cisplatin produces marked nausea and vomiting in almost all 
           patients, which can usually be controlled with anti-emetics.  
           However, if it is severe or persistent, a reduction or 
           discontinuation of the treatment may be necessary. 
           
            Ototoxicity 
           
           Cisplatin can cause ototoxicity; tinnitus and decreased 
           ability to hear normal conversation may be used as 
           indicators.  Children are particularly sensitive. 
           
           Ototoxicity, as induced by cisplatin, is cumulative so 
           therapy is contraindicated in patients with pre-existing 
           hearing impairments. Patients with moderate degrees of 
           hearing loss should have their doses altered if therapy were 
           continued (Huang & Schacht, 1991). 
           
            Hypomagnesaemia and Hypocalcaemia 
           
           As cisplatin can cause hypomagnesaemia and hypocalcaemia, 
           these should be corrected prior to the start of therapy. 
           
            Anaemia 
           
           Cisplatin can cause a decrease of greater than 2 g per cent 
           haemoglobin during repeated courses of therapy; treatment 
           should proceed with extreme caution. 
           
            Neurotoxicity
           
           Peripheral neuropathies can occur during cisplatin therapy 
           and are usually sensory and reversible.  In some cases they 
           become progressive and irreversible.  This latter type is 
           seen generally after prolonged therapy (4 to 7 months) and 
           cessation of therapy is generally recommended.
           
            Anaphylaxis
           
           Patients with a family or personal history of atopy are at 
           particular risk.  People who have pre-existing asthma or 
           related conditions should be treated with care. 
           
            Precautions
           
                 Extreme care should be taken by persons preparing and 
           administering cisplatin and those handling the urine of 
           treated patients. 
           
           Preparation of cisplatin infusions etc. should be done only 
           in an approved biological safety cabinet using protective 
           clothing.
           
                 Cisplatin is carcinogenic in animals.  Care must be
           exercised in regards to handling cisplatin.

    5. ROUTES OF ENTRY

       5.1 Oral

           Cisplatin is not effective when administered orally (Gilman 
           et al., 1985). 

       5.2 Inhalation

           No data available.

       5.3 Dermal

           Cisplatin is not administered dermally.  Avoid dermal contact
           and absorption during administration.

       5.4 Eye

           Eye contamination may be a possible source of poisoning during
           intravenous administration of cisplatin.

       5.5 Parenteral

           Cisplatin is only available in the injectable form.  The 
           parenteral routes, intravenous, intra-arterial and 
           intraperitoneal, have all been used in cisplatin therapy and 
           poisoning would most likely occur by these three routes. 

       5.6 Others

           No data available.

    6. KINETICS

       6.1 Absorption by route of exposure

            Intravenous
           
           Totally absorbed after intravenous use.
           
           Rapid intravenous injection of cisplatin over 1 to 5 minutes 
           or rapid intravenous infusion over 15 minutes or one hour, 
           results in peak plasma concentrations immediately.
           
           When cisplatin is administered by intravenous infusion over 6 
           to 24 hours the plasma concentrations of total platinum 
           increase gradually during the infusion and reach peak 

           concentrations immediately following the end of the 
           infusions.
           
           When mannitol is given at the same time as cisplatin, the 
           peak plasma concentrations of non protein-bound platinum 
           appears to be increased. 
           
           Intra-arterial
           
           When cisplatin is administered by intra-arterial infusion, 
           the local tumour exposure of the drug is increased as 
           compared with intravenous administration. 
           
           Intraperitoneal
           
           Cisplatin is rapidly and well absorbed systemically following 
           intraperitoneal administration.  This route gives 50 to 100% 
           plasma concentration in comparison with intravenous route.  
           Intraperitoneal fluid concentration of the drug is greatly 
           increased as compared with intravenous administration 
           (McEvoy, 1992). 

       6.2 Distribution by route of exposure

           Following the intravenous administration of Cisplatin, the 
           drug is widely distributed into body fluids and tissues.  The 
           highest concentrations can be seen in the kidneys, liver and 
           intestines, and can persist for up to 2 to 4 weeks.  However, 
           concentrations can also be found in the muscles, bladder, 
           testes, prostate, pancreas and spleen. 
           
           Cisplatin has also been found in the following tissues; small 
           and large intestines, adrenals, heart, lungs, lymph nodes, 
           thyroid, gall bladder, thymus, cerebrum, cerebellum, ovaries 
           and uterus. 
           
           Platinum appears to accumulate in body tissues following 
           administration of cisplatin and has been detected in many of 
           these tissues for up to 6 months after the last dose of the 
           drug.  Platinum also has been found in leucocytes and 
           erythrocytes. 
           
           The volume of distribution: 41 L/m2 (range 20 to 80 L/m2)
           (McEvoy, 1992).
           
           Cisplatin and any platinum-containing products are rapidly 
           and extensively bound to tissue and plasma proteins, 
           including albumin, gamma-globulins and transferrin. 
           
           Binding to tissue and plasma proteins appears to be 
           essentially irreversible with the bound platinum remaining in 
           plasma during the lifespan of the albumin molecule.  Protein 
           binding increases with time and less than 2 to 10% of 
           platinum in blood remains unbound several hours after 
           intravenous administration of cisplatin. 
           
           The extent of protein binding is about 90% and this occurs 
           essentially within the first two hours after a dose (McEvoy, 
           1992; Speight, 1987; NDIS, 1985).
           
           Penetration into the central nervous system (CNS) does not 
           occur readily.  The resultant levels are low in the CNS, but 
           significant amounts of cisplatin can be detected in 
           intracerebral tumour tissue and oedematous brain tissue 
           adjacent to the tumour.  In healthy brain tissue levels 
           appear to be low (McEvoy, 1992; NDIS, 1985).

       6.3 Biological half-life by route of exposure

           The distribution half life: 8 to 10 minutes (NDIS, 1985).
           
           The elimination half life: 40 to 45 minutes (NDIS, 1985).
           
           Monophasic elimination half life: 0.3 to 0.5 hours (NDIS,
           1985; Speight, 1987)
           
           Terminal half life of total platinum in a patient with severe 
           renal failure: 1 to 240 hours (NDIS, 1985; Speight, 1987).
           
           Total platinum (adults with normal renal function): 8.1 to 49 
           minutes (initial phase); 30.5 to 107 hours (or longer) in 
           terminal phase (McEvoy, 1992).
           
           Non protein bound platinum: 2.7 to 30 minutes in the initial
           phase and 32 to 53.5 minutes in the terminal phase.
           
           After a 6-hour intravenous infusion in patients with normal 
           renal function the terminal plasma elimination half life for 
           the total platinum is 73 to 290 hours (McEvoy, 1992).
           
           In acute oliguric renal failure requiring haemodialysis the 
           terminal plasma half life of total platinum was approximately 
           10 days (McEvoy, 1992).
           
           In children with normal renal function, the serum elimination 
           half lives of total platinum averages about 25 minutes in the 
           initial phase and 44 hours in the terminal phase.  The serum 
           elimination half-life of non protein bound platinum averages 
           1.3 hours. 

       6.4 Metabolism

           The metabolic fate of cisplatin has not been completely 
           elucidated.  There is little evidence to date that the drug 
           undergoes enzymatic biotransformation. The cisplatin molecule 
           has chloride ligands on it and it is believed that these are 
           displaced by water thus forming positively charged platinum 
           complexes that react with nucleophilic sites. Their rate and 
           extent depends on the strength, concentration and 
           accessibility of the nucleophiles.  The chemical identities 
           of the metabolites of cisplatin have been found but have yet 

           to be identified. There is a strong possibility that 
           cisplatin and its metabolites undergo enterohepatic 
           circulation (McEvoy, 1992). 

       6.5 Elimination by route of exposure

           Intact cisplatin and its metabolites are excreted principally 
           in urine.  It occurs predominantly via glomerular filtration 
           but there is some evidence that secretion and reabsorption of 
           cisplatin and its metabolites also occurs.
           
           Initially renal clearance of total platinum equals creatinine 
           clearance and represents elimination of non-protein bound 
           platinum molecules including intact cisplatin.
           
           As extensive protein binding occurs then clearance declines 
           rapidly, resulting in a prolonged excretory phase.
           
           The ultimate rate of fall of total plasma platinum 
           concentration is governed by the rate of degradation of 
           plasma proteins bearing bound platinum.
           
           A small amount of cisplatin is excreted via the bile and 
           saliva (McEvoy, 1992).
           
           After a dose of cisplatin:
           
           15 to 30% of the dose is excreted in the urine in the first 2
           to 4 hours (of which 90% is intact cisplatin)
           
           20 to 80% of the dose is recovered in the first 24 hours
           (NDIS, 1985).
           
            Elimination half-life of cisplatin (Adults) (Speight, 1987)
           
           Normal renal function:        2 to 72 hrs
           Endstage renal disease:       1 to 240 hrs
           
           Percent excreted unchanged:  25 to 75%

    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of Action

           7.1.1 Toxicodynamics

                 Cisplatin appears to be cycle-phase nonspecific and 
                 will cause cell death in all cells.  It is in those 
                 cells which turn over rapidly (tumour cells, skin 
                 cells, gastrointestinal cells, bone marrow cells) that 
                 cell death will occur at a faster rate than other cells 
                 with a slower turnover rate (e.g. muscle cells). 
                 
                 Cisplatin exerts its antineoplastic activity when it 
                 has the cis-configuration and without a charge on the 
                 molecule.  The trans-configuration is inactive. 

           7.1.2 Pharmacodynamics

                 Cisplatin complex moves through cell membranes in an 
                 unionised form and this is achieved in the relatively 
                 high chloride concentration in the plasma.
                 
                 Intracellularly the concentration of chloride ions is 
                 lower than in the plasma and the chloride ligands on 
                 the cisplatin complex are displaced by water.  The 
                 result is the formation of positively charged platinum 
                 complexes that are toxic to cells. 
                 
                 The cisplatin molecule binds to the DNA molecule at the 
                 guanine bases and thus inhibits DNA synthesis, protein 
                 and RNA synthesis (the latter two are inhibited to a 
                 lesser degree). 
                 
                 The drug forms intrastrand and interstrand cross links 
                 in the DNA molecule and appears to correlate well with 
                 the cytotoxicity of the drug.  The tumour cells amass 
                 an overburden of mutations which lead eventually to the 
                 cell's death. 
                 
                 Cisplatin also has immunosuppressive, radiosensitizing 
                 and antimicrobial properties.
                 
                 The exact mechanism of action of cisplatin is not yet 
                 understood but the drug has biochemical properties 
                 similar to those of bifunctional alkylating agents. 
                 
                 (McEvoy, 1992; NDIS, 1985; Gilman et al., 1985; 
                 Prestayko, 1980) 

       7.2 Toxicity

           7.2.1 Human Data

                 7.2.1.1 Adults

                         The major toxicity caused during cisplatin 
                         treatment is dose related and cumulative.  For 
                         example, renal tubular function impairment can 
                         occur during the second week of therapy and if 
                         higher doses or repeated courses of cisplatin 
                         are given then irreversible renal damage can 
                         occur. 
                         
                         A minimum lethal dose has not been reported in 
                         the literature to date. 
                         
                         Hydration is required during therapy and this 
                         lessens the likelihood of nephrotoxicity and 
                         other toxicities. 
                         
                         With a dose of 100 mg/m2, without hydration, 
                         the problem of nephrotoxicity may become 
                         evident.
                         
                         Doses of greater than 100 mg/m2 of cisplatin 
                         are likely to cause moderate bone marrow 
                         toxicity in the form of suppression as well as 
                         nephrotoxicity. 

                 7.2.1.2 Children

                         No data available.

           7.2.2 Animal Data

                 Species      Route   LD 50 (mg/kg)
                 
                 Rat          IP          12.0
                              SC          45.0
                              IV           8.0
                 Mouse        IP           6.0
                              IV          12.0
                 Guinea Pig   IP           9.7
                 
                 IP - Intraperitoneal
                 SC - Subcutaneous
                 IV - Intravenous(NDIS, 1985)

           7.2.3 In-vitro data

                 No data available.

       7.3 Carcinogenicity

           Cisplatin is carcinogenic in animals so care must be 
           exercised in regards to handling cisplatin and wastes 
           associated with patients receiving cisplatin. 

       7.4 Teratogenicity

           There is positive evidence of human foetal risk, so the 
           benefits in pregnant women must be weighed against the risk 
           (Category D in Briggs et al., 1990). 

       7.5 Mutagenicity

           Cisplatin is mutagenic in bacterial cultures and produces 
           chromosome aberrations in animal cells in tissue culture 
           (NDIS, 1985).

       7.6 Interactions

           Aluminium
           
           All aluminium and aluminium alloys in IV sets, needles, 
           catheters and syringes form a black precipitate of platinum 
           (with a rapid loss of potency) when cisplatin is given 
           through these devices.
           
           Nephrotoxic drugs
           
           Cisplatin produces cumulative nephrotoxicity that can be 
           potentiated by nephrotoxic drugs, e.g. aminoglycosides, 
           cephalosporins and amphoteracin B, etc.
           
           Aminoglycosides
           
           Concurrent administration of aminoglycosides within 1-2 weeks 
           of cisplatin therapy has been associated with an increased 
           risk of nephrotoxicity and renal failure.  Therefore 
           aminoglycosides should be used with extreme care during 
           treatment.
           
           Other
           
           When in an aqueous solution, cisplatin reacts with a variety 
           of chemical molecules including bromide and iodide ions, 
           bisulphite etc. 
           
           Metabisulphite, found as a preservative in some parenteral 
           formulations can rapidly inactivate cisplatin.  Therefore 
           avoid admixture of cisplatin with other agents that may 
           contain excipients (NDIS, 1985). 
           
           There is a risk of potentiating cisplatin ototoxicity with 
           the other ototoxic drugs, e.g. aminoglycosides and loop 
           diuretics. 
           
           Studies in animals indicate that the antineoplastic activity 
           of cisplatin and some other antineoplastic agents can be 
           potentially synergistic.  The agents trialed were bleomycin, 
           doxorubicin, fluorouracil, methotrexate, vinblastine, 
           vincristine and etoposide (McEvoy, 1992). 

       7.7 Main Adverse Effects

           Numerous adverse effects during cisplatin therapy have been 
           reported in the literature. 
           
           Renal effects
           
           Nephrotoxicity is dose related and can be severe.  Cisplatin 
           should be administered with adequate intravenous hydration 
           and diuresis. 
           
           Renal toxicity is seen by an increase in serum creatinine, 
           BUN, serum uric acid and/or a decrease in creatinine 
           clearance and glomerular filtration rate. 
           
           Hypomagnesaemia and other electrolyte disturbances can be 
           seen during cisplatin therapy which is secondary to 
           cisplatin-induced renal dysfunction.
           
           Cisplatin increases the excretion of magnesium and calcium 
           and to a lesser extent potassium, zinc, copper and amino 
           acids.
           
           The symptoms of hypomagnesaemia include muscle irritability 
           or cramps, clonus, tremor, carpopedal spasm and/or tetany.  
           These symptoms can also persist for several months to years 
           post cisplatin therapy.
           
           Gastrointestinal
           
           Marked nausea and vomiting are seen during cisplatin therapy. 
           Cisplatin is considered to be amongst the most emetogenic 
           antineoplastic agents available. 
           
           Diarrhoea is also a side effect of cisplatin therapy and 
           occurs less frequently than nausea and vomiting.
           
           Otic effects
           
           Ototoxicity has occurred in patients receiving cisplatin 
           therapy and is manifested as tinnitus, with or without loss 
           of hearing and occasional deafness.  Fosfomycin, an 
           antibacterial antibiotic, appears to protect against 
           cisplatin-induced ototoxicity.  Ototoxicity tends to be more 
           severe in children than in adults.
           
           Cisplatin has also caused vestibular ototoxicity, i.e. 
           vertigo or vestibular dysfunction but it is a rare 
           occurrence.  Those patients with  pre-existing vestibular 
           dysfunction are most at risk. 
           
           Neurotoxicity
           
           Peripheral neuropathies have been noted during cisplatin 
           therapy and manifest themselves as paraesthesia of the upper 
           and lower extremities and other sensory functions.
           
           Peripheral neuropathies generally occur only after prolonged 
           (4 to 7 months) treatment but their incidence rises if other 
           neurotoxic agents are used.
           
           Haematological effects
           
           Myelosuppression occurs in about 25 to 30% of patients and 
           manifests itself as leucopenia, thrombocytopenia and anaemia. 
           Myelosuppression can be cumulative and severe especially if 

           the patient has been previously treated with other 
           antineoplastic agents.
           
           Sensitivity Reactions
           
           Anaphylaxis has occurred during cisplatin therapy and has 
           occurred after 5 or more doses of the drug.  Some of the 
           manifestations include facial oedema, flushing, wheezing or 
           respiratory distress, tachycardia and hypotension etc. 
           
           These reactions have occurred after intravenous and 
           intravesical administration. 
           
           Cardiovascular effects
           
           Cardiovascular effects are rare but can be debilitating. 
           Symptoms include bradycardia, left bundle branch block, 
           congestive heart failure.  The vascular toxicities include 
           myocardial infarction, coronary artery disease, renovascular 
           lesions, cerebrovascular accidents and Raynaud's phenomenon.
           
           Ocular effects
           
           Optic neuritis, papilloedema and cerebral blindness are rare 
           occurrences in patients receiving cisplatin therapy. 
           
           Hepatic effects
           
           Mild and transient elevations of serum AST (SGOT) and ALT 
           (SGPT) concentrations are rare in cisplatin therapy.
           
           Local effects
           
           Local phlebitis may occur after intravenous use of cisplatin. 
           
           Local pain, oedema and erythema have also occurred following 
           intra-arterial infusion.
           
           (NDIS, 1985; Gilman et al., 1985; McEvoy, 1992) 

    8. PHARMACOLOGICAL, TOXICOLOGICAL AND OTHER ANALYSES

       8.1 Sample

           8.1.1 Collection

           8.1.2 Storage

           8.1.3 Transport

       8.2 Toxicological Analytical Methods

           8.2.1 Tests for active ingredient

           8.2.2 Tests for biological sample

       8.3 Other Laboratory analyses

           8.3.1 Biochemical Investigations

                 8.3.1.1 Blood

                         The manufacturers recommend  serum magnesium, 
                         potassium, calcium, urea and creatinine 
                         concentrations and BUN should be determined 
                         prior to each additional course of therapy.  
                         Peripheral blood counts should also be 
                         monitored at least weekly in patients using 
                         therapeutic doses of cisplatin. Liver function 
                         tests should also be performed regularly. 

                 8.3.1.2 Urine

                         The manufacturers recommend creatinine 
                         clearance be determined prior to beginning 
                         cisplatin therapy. 
                                           
                 8.3.1.3 Other

                         Visual and auditory tests should be performed 
                         throughout treatment with cisplatin. 

           8.3.2 Arterial Blood Gas Analysis

           8.3.3 Haematological or Haemostasiological Investigations 

                 Peripheral blood counts should be monitored at least 
                 weekly (as recommended by the manufacturers) during 
                 cisplatin therapy.  Cisplatin has the potential to 
                 cause myelosuppression and the blood counts will give 
                 an indication of how severely the condition has 
                 progressed. 

           8.3.4 Other Relevant Biomedical Analyses

                 ECG and other cardiac monitoring devices should be 
                 employed to enable electrolyte and cardiac disturbances 
                 to be recognised. 

       8.4 Interpretation

           Cisplatin induces nephrotoxicity with hypomagnesaemia, 
           hypocalcaemia and hypokalaemia as manifestations.  By 
           interpreting blood and urine electrolyte concentrations the 
           degree of toxicity can be determined.
           
           Auditory tests can give an indication of the ototoxicity 
           caused by cisplatin and doses should be postponed or reduced 
           as indicated.
           
           Peripheral blood counts indicate the degree of 
           myelosuppression and carcinoma treatment should not continue 
           if these counts are not within the normal ranges (McEvoy, 
           1992; Gilman et al., 1985; NDIS, 1985). 

    9. CLINICAL EFFECTS

       9.1 Acute Poisoning

           9.1.1 Ingestion

                 Cisplatin is not effective when administered orally. 
                 This route would not be a likely source of poisoning 
                 (Gilman et al., 1985). 

           9.1.2 Inhalation

                 No data available.

           9.1.3 Skin Exposure

                 Dermal contact absorption can occur during 
                 administration to either the operator or the patient 
                 receiving the drug.
                 
                 Local necrosis following cisplatin extravasation has 
                 been reported.
                 
                 Also a pruritic erythematous macular rash and non 
                 infectious pyoderma have been reported in the 
                 literature. 
                 
                 (NDIS, 1985; Gilman et al., 1985; McEvoy, 1992; 
                 Reynolds, 1989) 

           9.1.4 Eye Contact

                 Necrosis is a possible effect when cisplatin is given 
                 by the intravenous route.
                 
                 Cisplatin can cause papilloedema and retrobular 
                 neuritis following systemic administration. 

           9.1.5 Parenteral Exposure

                 Intravenous, intraperitoneal and intra-arterial routes 
                 have all been used in cisplatin therapy and it is by 
                 these routes that poisoning is most likely to occur.
                 
                 Adequate pretreatment and post treatment hydration 
                 (with intravenous fluids and diuresis) and maintenance 
                 of adequate urinary output must be ensured throughout 
                 cisplatin therapy to help minimise renal complications.  
                 The hypothesis is that this regimen dilutes the 

                 cisplatin metabolite concentrations in the kidney and 
                 lessens the incidence of toxicity to the cells.
                 
                 Renal toxicity is manifested by an increase in serum 
                 creatinine, BUN, serum uric acid and/or a decrease in 
                 creatinine clearance and glomerular filtration rate.
                 
                 The renal impairment is a direct result of cisplatin 
                 induced renal tubular damage leading ultimately to 
                 renal failure.
                 
                 Disturbances have been seen in serum electrolytes due 
                 principally to cisplatin induced renal tubular 
                 dysfunction. Patients subsequently develop 
                 hypomagnesaemia, hypocalcaemia and hypokalaemia and to 
                 a lesser extent hypophosphatemia and hyponatremia.
                 
                 Cisplatin produces marked nausea and vomiting in almost 
                 all patients to the extent that some patients 
                 experience anticipatory nausea and vomiting.  Diarrhoea 
                 has also occurred but with less frequency than nausea 
                 and vomiting.
                 
                 Ototoxicity develops in various degrees on cisplatin 
                 therapy.  In larger and prolonged dosing with cisplatin 
                 the ototoxicity can be irreversible.  Although this is 
                 not a life threatening event, it can be severe enough 
                 for patients to refuse further antineoplastic therapy.
                 
                 The haematological effects of cisplatin are usually 
                 moderate and reversible.
                 
                 Myelosuppression is a common problem seen as 
                 leucopenia, thrombocytopenia and anaemia and if severe 
                 enough can cause the death of the patient.
                 
                 Myelosuppression can be cumulative so care must be 
                 exercised during cisplatin therapy so that the 
                 patient's blood counts can return to normal levels 
                 before the next dose of cisplatin is due.
                 
                 Anaphylactoid reactions can occur when cisplatin is 
                 given and the manufacturer recommends that if they 
                 occur, cisplatin administration should be stopped 
                 immediately.
                 
                 Cardiovascular effects are rare but include 
                 bradycardia, left bundle branch block and congestive 
                 heart failure.
                 
                 Hepatic enzyme concentrations in the sera become 
                 elevated including AST (SGOT) and ALT (SGPT). 

           9.1.6 Other

                 No data available.

       9.2 Chronic poisoning

           9.2.1 Ingestion

                 No data available.

           9.2.2 Inhalation

                 No data available.

           9.2.3 Skin data

                 No data available.

           9.2.4 Eye Contact

                 No data available.

           9.2.5 Parenteral Exposure

                 Renal toxicity is cumulative and seen usually after 
                 several courses of cisplatin therapy.  Disturbances in 
                 electrolytes can be a long term manifestation due to 
                 cisplatin induced renal tubular dysfunction.
                 
                 Ototoxicity develops and is cumulative especially after 
                 repeated high doses of cisplatin or when other ototoxic 
                 drugs are given concurrently.  Although this is not 
                 life threatening it can be irreversible.
                 
                 Haematological effects of cisplatin are cumulative 
                 especially if the blood forming cells are not allowed 
                 to recover after the course of treatment.  Vigorous 
                 treatments to prevent infections during the period of 
                 myelosuppression will be required if the patient is to 
                 survive. 

           9.2.6 Other

                 No data available.

       9.3 Course, prognosis and cause of death

           When an overdose of cisplatin is given the adverse effects 
           are not seen until days after the initial event, although 
           nausea and vomiting may occur initially. 
           
           The effects of myelosuppression can be seen starting about 
           one week after the overdose event.  During this time patients 
           would require, if needed, adequate antibiotic therapy to 
           prevent infections.   
           
           The effects of nephrotoxicity can be seen immediately post 
           overdose and acute renal failure can be experienced days 
           later.  The electrolytes to be monitored include magnesium, 
           potassium and calcium, all of which are involved in the 
           normal cell's functioning.  Renal failure can lead, if not 
           treated, to the death of the patient. 
           
           The causes of death from an overdose of cisplatin include 
           myelosuppression, renal failure and tetany. 

       9.4 Systemic description of clinical effects

           9.4.1 Cardiovascular

                  Acute
                 
                 Cardiovascular effects are rare events during cisplatin 
                 therapy.  They can include bradycardia, left bundle 
                 branch block and ST-T-wave changes with congestive hear 
                 failure.  Postural hypotension associated with 
                 neurotoxicity has also occurred.
                 
                 Vascular toxicities have also occurred including 
                 myocardial infarction, coronary artery disease, 
                 renovascular lesions, cerebrovascular accidents or 
                 cerebral arteritis and Raynaud's phenomenon.  The 
                 mechanism for the vascular toxicity has been proposed 
                 as damage to the endothelial cells.
                 
                 ECG changes secondary to electrolyte disturbances also 
                 occur.
                 
                  Chronic
                 
                 No data available.

           9.4.2 Respiratory

                  Acute
                 
                 Hyperpnoea and acute respiratory failure have been 
                 reported (Fassoulaki & Pavlov, 1989).
                 
                  Chronic
                 
                 No data available.

           9.4.3 Neurological

                 9.4.3.1 Central Nervous System (CNS)

                          Acute
                         
                         Decreased hearing, "thick" speech, impairment 
                         of taste and numbness of hands was experienced 

                         by a 36-year-old man who received 480 mg/m2 of 
                         cisplatin.  Eighteen months later, he was no 
                         longer dysarthric and he could taste normally 
                         (Schiller 1989). 
                         
                         Gait disturbances, loss or reduction of deep 
                         tendon reflexes and seizures have also been 
                         reported.
                         
                         Disorientation, paranoia and agitation can be 
                         attributed to cisplatin therapy (Reynolds 
                         1989).
                         
                          Chronic
                         
                         No data available.

                 9.4.3.2 Peripheral Nervous System

                          Acute
                         
                         Sensory function loss, with loss of 
                         proprioception and vibratory sense in a 
                         stocking-glove distribution and motor function 
                         loss leading to ataxia have been seen with 
                         cisplatin dosing (Reynolds, 1989; Dorr & Fritz, 
                         1982). 
                         
                          Chronic
                         
                         No data available.

                 9.4.3.3 Autonomic Nervous System

                          Acute
                         
                         No data available.
                         
                          Chronic
                         
                         No data available.

                 9.4.3.4 Skeletal and smooth muscle

                          Acute
                         
                         Tetany secondary to electrolyte imbalance has 
                         been reported (Reynolds, 1989).
                         
                          Chronic
                         
                         No data available.

           9.4.4 Gastrointestinal

                  Acute
                 
                 Cisplatin is a potent emetogenic and induces marked 
                 nausea and vomiting in almost all patients. 
                 
                 The nausea and vomiting appears to be mediated via a 
                 central mechanism and usually commences 1 to 6 hours 
                 post administration of cisplatin and continues for up 
                 to 24 hours or longer.  The nausea and anorexia can 
                 persist for up to 5 to 10 days in some patients. 
                 
                 Cisplatin can also cause diarrhoea.
                 
                 A metallic taste has also been reported in some 
                 patients. 
                 
                  Chronic
                 
                 No data available.

           9.4.5 Hepatic

                  Acute
                 
                 Serum AST (SGOT) and ALT (SGPT), bilirubin, alkaline 
                 phosphatase concentrations can become elevated during 
                 cisplatin therapy and it appears to be mild and 
                 transient. 
                 
                 Reversible liver toxicity has occurred (McEvoy, 1992; 
                 Dorr & Fritz, 1982).
                 
                  Chronic
                 
                 No data available.

           9.4.6 Urinary

                 9.4.6.1 Renal

                          Acute
                         
                         Nephrotoxicity is dose related, can be severe 
                         and is most often reversible.  It is manifested 
                         by renal tubular damage resulting in an 
                         elevation of the BUN, serum creatinine, serum 
                         uric acid and/or a decrease in creatinine 
                         clearance and glomerular filtration rate. 
                         
                         The peak detrimental effect on renal function 
                         usually occurs between the 10th and 20th days 
                         after treatment. Patients concomitantly 
                         receiving other nephrotoxic agents, eg 

                         aminoglycosides, have been shown to be at a 
                         greater risk of developing renal failure (Dorr 
                         & Fritz, 1982). 
                         
                         Hypomagnesaemia, hypocalcaemia, hypokalaemia 
                         have all been experienced during therapy. 
                         
                         Hyperuricemia has also occurred but secondary 
                         to impaired tubular transport of uric acid.  
                         This increase in uric acid is seen with the 
                         increased tumour breakdown during therapy. 
                         
                          Chronic
                         
                         No data available.

                 9.4.6.2 Others

                         No data available.

           9.4.7 Endocrine and Reproductive Systems

                  Acute
                 
                 Gynaecomastia is a rare occurrence following 
                 combination chemotherapy including cisplatin.
                 
                 Transient or permanent sterility has also been noted 
                 (McEvoy, 1992).
                 
                  Chronic
                 
                 No data available.

           9.4.8 Dermatological

                 Pruritic erythematous macular rashes have been reported 
                 as well as non infectious pyoderma (McEvoy, 1992).

           9.4.9 Eye, Ear, Nose, Throat: Local effects

                  Acute
                 
                 Papilloedema, cerebral blindness and optic neuritis 
                 have occurred during combination therapy with cisplatin 
                 and other antineoplastic agents but it is a rare 
                 occurrence. 
                 
                 Improvement and/or total recovery usually occurs when 
                 cisplatin is discontinued but children and patients 
                 with abnormal pre-treatment audiograms are most at risk 
                 and sometimes severe impairment may not be reversible 
                 (McEvoy, 1992; NDIS, 1985).
                 
                 Tinnitus and the decreased ability to hear normal 
                 conversations are observed during cisplatin therapy.
                 
                 Ototoxicity is seen more frequently in patients with 
                 pre-existing hearing impairment, concomitant 
                 administration of other ototoxic substances, eg 
                 aminoglycosides, and with higher doses of cisplatin.
                 
                 Tinnitus is usually transient and can persist from 
                 several hours to up to a week post therapy with 
                 cisplatin. 
                 
                 Hearing loss is usually bilateral and normally occurs 
                 at 4000 to 8000 Hz, progressing with time to lower 
                 frequencies.  The auditory damage appears to be due to 
                 degenerative changes in cochlear hair cells (McEvoy, 
                 1992).
                 
                  Chronic
                 
                 No data available.

           9.4.10 Haematological

                   Acute
                  
                  Myelosuppression, which is manifested by leucopenia, 
                  thrombocytopenia and anaemia has been noted in about 
                  25 to 30% of patients receiving cisplatin therapy.
                  
                  Myelosuppression may be cumulative and more severe in 
                  those patients previously treated with antineoplastic 
                  agents, radiotherapy/cisplatin or already 
                  immunocompromised. 
                  
                  Leucopenia and thrombocytopenia are dose related and 
                  become more pronounced when the dose of cisplatin is 
                  greater than 50 mg/m2. Leucocyte and platelet nadirs 
                  generally occur 18 to 23 days (range of 7.2 to 45 
                  days) following a single dose of cisplatin, with 
                  levels returning to pre-treatment levels in most 
                  patients within 39 days (range 13 to 62 days).  
                  Subsequent courses of cisplatin should not be 
                  instituted until platelets are present at levels 
                  greater than 100,000/mm3 and white cells greater than 
                  4000/mm3.
                  
                  Anaemia (decrease of greater than 2 g percent 
                  haemoglobin) occurs in a significant number of 
                  patients but usually after several courses of 
                  treatment. 
                  
                  The anaemia is of the normochromic - normocytic type 
                  and frequently returns to normal on cessation of 

                  therapy. Transfusions may be indicated in severe cases 
                  of anaemia. 
                  
                  Cisplatin has been shown to sensitise red blood cells 
                  and sometimes results in a direct Coombs positive 
                  haemolytic anaemia.  It has been suggested that 
                  anaemia caused by cisplatin may have resulted from a 
                  drug induced decrease in erythropoietin or erythroid 
                  stem cells.  There is also some evidence that both 
                  haemolysis and decreased erythropoiesis may contribute 
                  to the anaemia (Dorr & Fritz, 1982; McEvoy, 1992; 
                  NDIS, 1985; Reynolds, 1989).
                  
                   Chronic
                  
                  Myelosuppression and anaemia have been reported to be 
                  cumulative especially if courses of cisplatin are 
                  given more frequently than every 3 to 4 weeks.  This 
                  interval allows the bone marrow suppression to reverse 
                  (Dorr & Fritz, 1982; NDIS, 1985; McEvoy, 1992).

           9.4.11 Immunological

                   Acute
                  
                  Anaphylactoid reactions have occurred during therapy 
                  with cisplatin.  Those patients with a history atopy 
                  are particularly at risk.  The reaction is 
                  characterised by facial oedema, wheezing, tachycardia, 
                  hypotension and skin rash of urticarial nonspecific 
                  maculopapular type.  These all can occur within a few 
                  minutes of administration. 
                  
                  The anaphylactoid reactions usually occur after about 
                  5 doses of cisplatin.  The mechanism of action is not 
                  yet known but the reactions appear to be immune 
                  mediated in some patients (McEvoy, 1992; NDIS, 1985; 
                  Dorr & Fritz, 1982).
                  
                   Chronic
                  
                  Anaphylactoid reactions would occur after repeated 
                  courses of cisplatin especially in those patients with 
                  a history of atopy. 

           9.4.12 Metabolic

                  9.4.12.1 Acid Base disturbances

                            Acute
                           
                           A 59-year-old female experienced hypocapnia 
                           with the with the resultant acid-base 
                           disturbances during an overdose of cisplatin.  
                           It was postulated that the cisplatin crossed 

                           the blood-brain barrier and had a direct 
                           effect on the respiratory centre (Fassoulaki 
                           & Pavlov, 1989). 
                           
                            Chronic
                           
                           No data available.

                  9.4.12.2 Fluid and Electrolyte Disturbances

                            Acute
                           
                           Cisplatin can cause severe electrolyte 
                           disturbances, principally hypomagnesaemia, 
                           hypocalcaemia and hypokalaemia. 
                           Hypophosphatemia and hyponatremia have also 
                           occurred but to a lesser degree. 
                           
                           The disturbance in electrolytes is a direct 
                           result of cisplatin induced renal tubular 
                           dysfunction. 
                           
                           Cisplatin causes marked excretion of calcium 
                           and magnesium as well as potassium, zinc, 
                           copper and amino acids. The mechanism is not 
                           known but it may be a specific drug-induced 
                           membrane or transport system defect.
                           
                           Hypomagnesaemia and hypocalcaemia can occur 
                           during cisplatin therapy or within 3 to 4 
                           weeks post administration. The severity of 
                           hypomagnesaemia increases with each 
                           subsequent course of cisplatin.
                           
                           Children are particularly sensitive to 
                           cisplatin and tend to develop hypomagnesaemia 
                           more readily than adults.  The effects of 
                           hypomagnesaemia and hypocalcaemia include 
                           muscle irritability or cramps, clonus, 
                           tremor, carpopedal spasm and/or tetany.
                           
                           Hyperuricemia may occur in patients 
                           principally as a result of cisplatin induced 
                           nephrotoxicity. 
                           
                           Hyperuricemia is more pronounced when doses 
                           of cisplatin exceed 50 mg/m2 and peak serum 
                           concentrations of uric acid generally occur 
                           3 - 5 days after the administration of the 
                           drug (McEvoy, 1992; NDIS, 1985; Reynolds, 
                           1989).
                           
                            Chronic
                           
                           Hypomagnesaemia has persisted for several 
                           months to years after cisplatin therapy has 
                           been discontinued, and in some patients the 
                           effect has lasted longer than three years 
                           (McEvoy, 1992). 

                  9.4.12.3 Other

                            Acute
                           
                           Other adverse effects associated with 
                           cisplatin therapy include alopecia, myalgia, 
                           pyrexia, and gingival platinum line. 
                           Cisplatin has also been associated with the 
                           occurrence of the Syndrome of Inappropriate 
                           Antidiuretic Hormone Secretion (SIADH). 

           9.4.13 Allergic Reactions

                  See Section 9.4.11

           9.4.14 Other Clinical Effects

                  No data available.

           9.4.15 Special risks

                   Pregnancy
                  
                  There is positive evidence of human foetal risks but 
                  the benefits from use in pregnant women may be 
                  acceptable despite the risk (Category D1 "A Reference 
                  Guide to Foetal and Neonatal Risk in Pregnancy & 
                  Lactation", Briggs et al., 1990).
                  
                  Pregnancy is a relative contraindication in the use of 
                  cisplatin because of its mutagenic effects on 
                  bacterial cell cultures.  It also causes chromosome 
                  aberrations in animal cells in tissue culture (NDIS, 
                  1985).
                  
                   Breastfeeding
                  
                  Breastfeeding is not recommended during cisplatin 
                  therapy due to potential risk to the infant (Briggs et 
                  al., 1990). 
                  
                   Enzyme Deficiencies
                  
                  No data available.

    10. MANAGEMENT

       10.1 General Principles

            Treatment is supportive and symptomatic.  Patients should be 
            monitored for at least 3 to 4 weeks in case of delayed 
            toxicity. 
            
            The anticipated complications would be nephrotoxic, 
            ototoxic, neurotoxic and haematotoxic. 
            
            There is no specific antidote to use in cisplatin toxicity. 
            
            Hydration with 3 to 6 L intravenous fluids/day and 
            intravenous mannitol, which increases the urinary volume and 
            thus decrease the effective urinary concentration of 
            platinum and its metabolites, is recommended. 
            
            Monitor vital signs.  Renal and hepatic function, ECG, 
            haematological, otic and neurological functions should also 
            be monitored. Serum electrolyte concentrations and fluid 
            requirements should be monitored and corrected if required.
            
            The manufacturers recommend that serum magnesium, potassium, 
            calcium and creatinine concentrations, creatinine clearance 
            and BUN be determined prior to and during therapy. 
            
            The peripheral blood counts should be monitored as the 
            haematological effects can be slow in developing and 
            monitoring should be continued 3 to 4 weeks post incident.
            
            Although not a life threatening problem, ototoxicity can be 
            cumulative and persistent.  Auditory function tests should 
            be performed regularly. 

       10.2 Relevant laboratory analyses and other investigations

            10.2.1 Sample Collection

                   No data available.

            10.2.2 Biomedical analysis

                   Monitor electrolytes including magnesium, potassium, 
                   calcium, phosphate and creatinine levels.
                   
                   Monitor liver function tests.
                   
                   Monitor peripheral blood counts.
                   
                   Monitor cardiac functions.

            10.2.3 Toxicological analysis

                   No data available.

            10.2.4 Other Investigations

                   Auditory function tests can be performed to give an 
                   indication of ototoxicity. 

       10.3 Life Supportive procedures and symptomatic treatment

            Cisplatin causes myelosuppression to some degree in all 
            patients.  In the overdosed patient the haemopoietic system 
            should be supported.  Therapy would include packed cells and 
            other blood products. In immuno-compromised patients anti-
            infective prophylaxis may be indicated. 
            
            Correction of the electrolyte imbalances to prevent serious 
            secondary effects should be monitored. 
            
            Correction of the nausea and vomiting episodes to avoid 
            gastro-oesophageal mechanical tears and electrolyte 
            imbalances. 

       10.4 Decontamination

            Wash all cisplatin-contaminated areas with copious amounts 
            of water or irrigation fluids.  The irrigation should last 
            for at least 15 minutes when eye exposure is suspected.  
            
            Oral ingestion of cisplatin has not yet been reported but if 
            this occurs then emesis, gastric lavage and activated 
            charcoal should be instigated. 
            
            If cisplatin is spilled, wipe up spillage with disposable 
            sponges which should be incinerated.  Any remainder may be 
            inactivated with sodium tetraborate 2% stabilised with 0.2% 
            sodium hydroxide (this solution is stable for one week). 

       10.5 Elimination

            Adequate hydration with 3 to 6 litres of intravenous fluids 
            should be given when cisplatin is administered, together 
            with mannitol and diuretics (e.g. frusemide).  This 
            maintains adequate urine output as well as having cisplatin 
            diluted in the urine. 
            
            Haemodialysis has been tried but because cisplatin rapidly 
            becomes protein bound it is of little value. 

       10.6 Antidote

            10.6.1 Adults

                   To date there is no antidote available for cisplatin 
                   overdose. 

            10.6.2 Children

                   To date there is no antidote available for cisplatin 
                   overdose. 

       10.7 Management discussion

            Extreme caution should be taken by persons handling 
            biological fluids and wastes of treated patients (either in 
            normal therapy or in overdose cases). 
            
            If the plasma proteins to which cisplatin has become bound 
            could be removed (e.g. plasma exchange) then this may be an 
            effective method of reducing the cisplatin burden. 

    11. ILLUSTRATIVE CASES

        11.1 Case reports from the Literature

             Case 1
             
             Fassoulaki & Pavlov (1989) - a 59-year-old patient with 
             advanced ovarian carcinoma was given in error 150 mg of 
             cisplatin for three consecutive days instead of 50 mg/day 
             for three days (a total dose of 450 mg was given within 
             three days).  On day four following the cisplatin 
             overdosage the patient developed numbness of the upper and 
             lower limbs, headache and hyperpnoea.  Electrocardiogram, 
             central venous pressure, direct arterial blood pressure and 
             urine output were monitored continuously.  The patient 
             became unconscious and was thus intubated and ventilated 
             mechanically.  The K+ and PO4- renal losses were 
             significant and K+ daily replacement reached 18 g/day.  
             Myelosuppression developed and in treatment received 26 
             units of platelets and 9 units of blood.  The patient's 
             recovery was complete except for a hearing impairment. 
             
             Case 2
             
             Schiller et al. - A 36-year-old white male developed 
             testicular choriocarcinoma for which he was to receive 
             cisplatin.  On the third cycle he inadvertently received a 
             continuous infusion of 40 mg/m2 every eight hours for 4 
             days (198 mg/day = 480 mg/m2) instead of 40 mg/m2 /day 
             divided into three equal eight-hour infusions.  
             Complications included myelosuppression, neurotoxicity, 
             ototoxicity and nephrotoxicity. Treatment included broad-
             spectrum antibiotics when the patient became febrile, 
             intensive parenteral hydration, mannitol diuresis and 
             administering the drug in hypertonic saline.  The patient 
             recovered from the event but had residual ototoxicity.
             
             Case 3
             
             A 59-year-old woman with metastatic adenocarcinoma was 
             given hydroxyurea and cisplatin every three weeks.  Four 
             days after the third case of treatment the patient 
             developed confusion and then status epilepticus.  The  
             total cumulative dose of cisplatin was 225 mg/m2. She 
             remained unconscious for 36 hours despite treatment.  On 
             the fifth day she regained consciousness but had reduced 
             visual acuity of 6/60 bilaterally. The visual acuity slowly 
             improved and was normal by the tenth day (Clin Alert, 
             1991a). 
             
             Case 4
             
             A 26-year-old man with an abdominal mass and two pulmonary 
             nodules was given cisplatin, etoposide and bleomycin in 
             conventional doses.  After the third cycle of the regimen, 
             the patient noted a transitory speech disorder and weakness 
             of the left arm on discharge from hospital.   He was 
             readmitted to hospital with motor aphasia, left hemiparesis 
             and right-sided Jackson seizures.  An occlusion of the 
             right middle cerebral artery was suspected and confirmed.  
             A thrombectomy was performed but the patient deteriorated 
             and died from uncontrollable cerebral oedema (Clin Alert, 
             1991b). 

        11.2 Internally extracted data on cases

             No data available. 

        11.3 Internal Cases

             To be added by the centre

    12. ADDITIONAL INFORMATION

        12.1 Availability of Antidotes

             There is no recommended antidote available for cisplatin 
             overdose. To be added by the centre. 

        12.2 Specific Preventative Measures

             No data available.

        12.3 Other

             No data available.
             
    13. REFERENCES
          
        Briggs GG, Freeman RK & Yaffe SF (1990) A reference guide to 
        fetal and neonatal risk drugs in pregnancy and lactation, 3rd 
        ed. Baltimore, Williams and Wilkins.
        
        Budavari S ed. (1989) The Merck index, an encyclopedia of 
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 
        Merck and Co., Inc. p 361.
        
        Clin-Alert (1987) Cisplatin - Anaemia. Vol No 9, May 15, No 116.
        
        Clin-Alert (1989) Fluorouracil - Cardiac toxicity. Vol No 24, 
        Dec 31, No 320 
        
        Clin-Alert (1990a) Bleomycin and cisplatin - arterial 
        thrombosis. Vol No 11, June 15, No 135
        
        Clin-Alert (1990b) Cisplatin - Neurotoxicity. Vol  No 17, Sept 
        14, No 224 
        
        Clin-Alert (1991a) Cisplatin - convulsions and transient 
        cortical blindness. Vol No 8, April 26, No 102
        
        Clin-Alert (1991b) Cisplatin - Acute cerebrovascular event - 
        death.  Vol No 18, Sept 27,  No 240 
        
        David Bull Laboratories (1992) Cisplatin. Melbourne, 
        Manufacturers Literature. 
        
        Dorr RT & Fritz WL (1982) Cancer chemotherapy handbook. London, 
        Kimpton Medical. 
        
        ADRAC (1991) Drug induced hearing disorders. Australian Adverse 
        Drug Reactions Bulletin Volume 10 No 1, Canberra, Australian 
        Government Publishing Service. 
        
        Fassoulaki A & Pavlov H (1989) Overdosage intoxication with 
        cisplatin - a cause of acute respiratory failure.  Journal of 
        the Royal Society of Medicine, 82: 
        
        Gilman AG, Goodman LS, Rall TR & Murad F eds.(1985)  Goodman & 
        Gilman's the pharmacological basis of therapeutics. 7th ed. New 
        York, Macmillan Publishing Company. 
        
        Huang MY & Schacht J (1991) Drug induced ototoxicity. Current 
        Therapeutics, Vol. 32, No 10 October. 
        
        McEvoy GK ed. (1992) American hospital formulary service, drug 
        information.Bethesda, American Society of Hospital Pharmacists.
        
        National Drug Information Service (1985) NDIS Profile on 
        Cisplatin. Commonwealth Department of Human Services and Health, 
        Canberra.
        
        Prestayko AW, Crooke ST & Carter SK eds. (1980) Cisplatin 
        Current Status and New Developments, Academic Press. 
        
        Reynolds JEF ed. (1989) Martindale, the extra phamacopoeia 29th 
        ed. The Pharmaceutical Press.
        
        Schiller JH, Rozental J, Tutsch KD, & Trump D (1989)  
        Inadvertent administration of 480 mg/m2 of cisplatin.  The 
        American Journal of Medicine, 86:
        
        Speight TM ed. (1987)  Avery's drug treatment, principles and 
        practice of clinical pharmacology and therapeutics, 3rd ed. 
        Williams and Wilkins. 
        
        Thomas J ed. (1991)  Prescriptions products guide, Australian 
        Pharmaceutical Publishing Company Limited.
        
        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation,  p 
        125.
        
        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p 67. 

    14. AUTHOR(S), REVIEWER(S), DATE(S), COMPLETE ADDRESS(ES)

        Author     Ms A.E.F. Kaye
                   Tasmanian Poison Information Centre
                   Royal Hobart Hospital
                   GPO Box 1061L
                   Hobart 7001
                   Tasmania 
                   Australia
    
                   Tel: 61-02-388465
                   Fax: 61-02-312043
    
        Date       April 1992
    
        Reviewer   Dr K. Hartigan-Go
                   Department of Pharmacology
                   University of the Philippines Medical School
                   Pedro Gil Street
                   Manila
                   Philippines
    
        Date       July 1992
    
        Peer    London, United Kingdom, September 1992,
        review  (Drs Caitens, Critchley, Kaye, Maramba, Ombega, 
                Panganiban) 
    
                
    Surplus References

    Dreisbach RH & Robertson WO (1987) Handbook of poisoning 12th 
    Edition Lange. 

    Fischer DS & Knobf MT (1989) The Cancer chemotherapy handbook 3rd 
    ed. Year Book Medical Publishers. 

    Gosselin RE, Smith RP & Hodge HC (1984) Clinical toxicology of 
    commercial products. 5th ed., Baltimore, MD, Williams and Wilkins. 

    Kroben JE & Anderson PO (1983) Handbook of clinical drug data, 5th 
    Edition, Drug Intelligence Publications Inc. 

    Mollman JE (1990) Cisplatin Neurotoxicity. The New England Journal 
    of Medicine, 322 ( 2): 

    Richardson VE ed. (1989) Pharmacology and drug information for 
    nurses, 3rd ed. Society of Hospital Pharmacists of Australia, 
    Harcourt Brace Jovanovich. 

    Trissel LA (1990) Handbook on injectable drugs, 6th ed. Bethesda, 
    American Society of Hospital Pharmacists. 



    See Also:
       Toxicological Abbreviations
       Cisplatin (UKPID)
       Cisplatin  (IARC Summary & Evaluation, Supplement7, 1987)
       Cisplatin (IARC Summary & Evaluation, Volume 26, 1981)