MONOGRAPH FOR UKPID CISPLATIN Robie Kamanyire National Poisons Information Service (London Centre) Medical Toxicology Unit Guy's & St Thomas' Hospital Trust Avonley Road London SE14 5ER UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. 1 NAME 1.1 Substance Cisplatin 1.2 Synonyms CDDP, cis-DDP, Cis-Diamminedichloroplatinum, cis-Diamminedichloroplatinum (II), Cis-platin, cisplatinum, cis-Platinum, DDP, Peyrone's Chloride, Platinum Diamminodichloride, Diaminedichloroplatinum. 1.3 Therapeutic class Antineoplastic agent 1.4 Product Name(s) Abiplatin (Netherlands), Cisplatin (UK), Cisplatyl (France), Citoplatino (Italy), Lederplatin (Sweden), Neoplatin (Spain), Norplatin (South Africa), Placis (Spain), Platamine (Australia), Platiblastin (Germany), Platiblastine (Switzerland), Platinex (Germany, Italy), Platinol (Canada), Plastistil (Spain), Platistin (Sweden), Platosin (Netherlands), Pronto Platamine (Italy), Randa (Japan). 1.5 Reference number CAS-15663-27-1 NCI-c55776 NIOSH TP 2450000 NSC-119875 NK 801 1.6 Main manufacturers and/or importers David Bull Laboratories, Spartan Close, Tachbrook Pk, Warwick CV34 6RS (UK) Pharmacia Ltd, Davy Ave, Knowlhill, Milton Keynes, MK5 8PH (UK) Farmitalia Carlo Erba Ltd, Italia House, 23 Grosvenor Rd, St. Albans, Hertfordshire, AL1 3AW (Australia, Germany, Italy, S.Africa, Spain, Sweden, Switzerland, UK) Abic (Netherlands), Bellon (France), Bristol-Myers (Spain, Switzerland, USA), Bristol-Myers Squibb (Sweden, Switzerland), Bristol (Canada, Germany, Italy, Netherlands), Kayaku (Japan), Neva (Sweden), Noristan (South Africa), Pharmachemie (Netherlands), Rhone-Poulenc (Italy), Wasserman (Spain). 1.7 Presentation/formulation Cisplatin powder for injection: Yellowish-white freeze-dried cake in clear glass vials containing 10mg or 50mg cisplatin. The formulation also contains sodium chloride and mannitol. Cisplatin solution for injection: Clear, practically colourless solution in amber glass vials containing cisplatin 1mg/ml, sodium chloride 9mg/ml and mannitol 1mg/ml with a pH of 3.5-4.0. 2 SUMMARY The principal target organ for cisplatin toxicity is the kidney. This toxicity is manifested by reduced renal function and leads to serum electrolyte changes and pathological changes in the urine analysis. Doses of cisplatin which produce changes in renal function may cause no histopathological changes. Higher doses of the drug lead to interstitial nephritis. Cisplatin also causes bone marrow hypoplasia, is ototoxic and can cause autonomic neuropathy. Slight changes in liver function and histopathology are also observed following cisplatin therapy. Excessive dosage can cause protracted nausea, vomiting and diarrhoea, thirst and metallic taste Nephrotoxicity characterised by oliguria, azotaemia, renal tubular acidosis and acute renal failure may occur. Electrolyte disturbances include hypomagnesaemia, hypocalcaemia, hypophosphataemia and hypokalaemia or hyperkalaemia. Tinnitus, dizziness, high frequency hearing loss leading to total deafness, decreased visual acuity, papilloedema and cortical blindness may occur. Further neurotoxicity includes peripheral neuropathy with numbness, tingling and decreased vibratory sensation. Autonomic neuropathy may also occur with gait difficulties, involuntary movements and loss of deep tendon reflexes. Central nervous system toxicity includes confusion, extrapyramidal effects and focal convulsions progressing to grand mal convulsions. Other reported effects include tachycardia, hyperpnoea, acute respiratory failure, metabolic acidosis, transient elevation of alkaline phosphatase, serum bilirubin and AST may also occur. Cisplatin is usually administered in hospital and the administering clinician must monitor the patient for any signs and symptoms of toxicity. Protracted nausea and vomiting are the initial symptoms, nephrotoxicity characterised by oliguria, renal tubular acidosis and acute renal failure, is cumulative and increases with the total dose and duration of treatment. Electrolyte disturbances, particularly hypomagnesaemia and hypocalcaemia, may occur as a result of renal toxicity. Peripheral neuropathy occurs predominantly to the sensory fibres, further neurotoxicity occurs in the form of ototoxicity and visual toxicity, presenting as tinnitus, high frequency hearing loss and decreased visual acuity. Bone marrow depression may be severe, with decreased leucocyte and platelet counts. Anaemia is also seen. There is no specific antidote, treatment is symptomatic and supportive. Initially hydration is the most important aspect of treatment, volumes of 3-4 litres per day have been used in adults, whilst children have received 3L/m2/day (Haupt et al, 1989), to reduce the risk of nephrotoxicity. Severe nausea and vomiting may be managed with antiemetics (e.g. ondansetron, metoclopramide or buspirone). Patients should be monitored closely for signs and symptoms of toxicity, particularly ototoxicity, and changes in cardiac, liver, renal and neurological function. 3 PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Cisplatin is a synthetic compound first described by Peyrone as a chloride salt in 1845. It was not until 1965 when Rosenberg accidentally generated platinum salts in bacterial culture, that their antibiotic activity was discovered. Subsequently some of these salts were shown to inhibit solid sarcomas in mice. Clinical trials of what we now know as cisplatin began in 1971, and its main use is as a cytotoxic drug. 3.2 Chemical structure cis-Diamminedichloroplatinum Pt(NH3)2Cl2 Molecular weight: 300.1 3.3 Physical properties Yellowish white powder, slightly soluble in water (1 in 1000), insoluble in alcohol; sparingly soluble in dimethylformamide. A 0.1% solution in 0.9% saline has a pH of 4.5-6.0. The injectable preparation has a pH of 3.5-6.2. Unopened vials of the powder are stable at room temperature for 2 years and the reconstituted material for 20 hours at 27°C. When stored under recommended conditions commercially available cisplatin injection is stable for 17 months following date of manufacture; cisplatin injection remaining in the amber vial following initial entry is stable for 28 days when protected from light or for 7 days when stored under fluorescent light. The unopened vials of both freeze-dried powder and solution for injection should be stored at room temperature and protected from light. Solutions of cisplatin must not be cooled or refrigerated as cooling may result in precipitation. It is recommended that diluted infusion solutions of cisplatin be protected from light during administration. Cisplatin is degraded on contact with aluminium, and therefore aluminium containing equipment should not be used for administration of cisplatin. 4 USES 4.1 Indications Cisplatin is indicated only for the treatment of malignancies. It has useful antitumour activity in certain solid tumours including ovarian cancer and testicular teratoma. Other malignancies which may respond to cisplatin therapy include cancer of the cervix, breast, head and neck, bladder and lung (small cell). In most cases the best results are obtained when cisplatin is used in combination with another cytotoxic drug or combined with radiotherapy. 4.2 Therapeutic dosage 4.2.1 Adults The usual dose regimen of cisplatin when given as a single agent is 50-120 mg/m2 by intravenous infusion once every 3 to 4 weeks or 15-20 mg/m2 by intravenous infusion daily for five consecutive days every 3 to 4 weeks. The dosage may need to be adjusted if the drug is used in combination with other anti-tumour chemotherapy. With multiple drug schedules cisplatin is usually given in doses from 20 mg/m2 upward every 3 to 4 weeks. 4.2.2 Children The usual dose regimen of cisplatin when given as a single agent is 50-120 mg/m2 by infusion once every 3 to 4 weeks or 15-20 mg/m2 by intravenous infusion daily for five consecutive days every 3 to 4 weeks. The dosage may need to be adjusted if the drug is used in combination with other anti-tumour chemotherapy. With multiple drug schedules cisplatin is usually given in doses from 20 mg/m2 upward every 3 to 4 weeks. 4.3 Contraindications Because cisplatin is used to treat life-threatening malignancies, contraindications to its use are only relative and must be placed in the context of the patient's overall well-being. Contraindications are: 1) Renal failure 2) Severe bone marrow suppression 3) Peripheral neuropathy 4) Pregnancy 5) Hearing disorders 6) Allergic or anaphylactic-like reactions to platinum containing compounds. 5 HUMAN HEALTH EFFECTS - TOXICITY 5.1 Acute toxicity 5.1.1 Ingestion It is now generally held that cisplatin is not thought to be absorbed through the gastrointestinal tract (Anon, 1982), although preliminary reports suggest that it may occur in rats and mice (Siddik et al, 1984). 5.1.2 Inhalation No data available. 5.1.3 Dermal Droplet exposure of the skin to antineoplastic drugs rarely causes acute problems. Cisplatin is not absorbed through intact skin, however dermal exposure to cisplatin has resulted in skin irritation (Khan et al, 1975) and may cause corrosive burns. 5.1.4 Eye contact Intravitreal injection in rabbit eyes has shown that as much as 0.1mg can be injected without toxic effect (Grant, 1986). 5.1.5 Parenteral exposure Cisplatin is usually given intravenously, administration via intra-arterial (Maiese et al, 1992) and intraperitoneal (Howell et al, 1982) routes have been studied. Excess dosage can cause protracted nausea, vomiting and diarrhoea, thirst and metallic taste Nephrotoxicity characterised by oliguria, azotaemia, renal tubular acidosis and acute renal failure may occur. Electrolyte disturbances include hypomagnesaemia, hypocalcaemia, hypophosphataemia and hypokalaemia or hyperkalaemia. Tinnitus, dizziness, high frequency hearing loss leading to total deafness, decreased visual acuity, papilloedema and cortical blindness may occur. Further neurotoxicity includes peripheral neuropathy with numbness, tingling and decreased vibratory sensation. Autonomic neuropathy may also occur with, gait difficulties, involuntary movements and loss of deep tendon reflexes. Central nervous system toxicity includes confusion, extrapyramidal effects and focal convulsions progressing to grand mal convulsions. Other reported effects include tachycardia, hyperpnoea, acute respiratory failure, metabolic acidosis, transient elevation of alkaline phosphatase, serum bilirubin and AST may also occur. 5.1.6 Other No data available. 5.2 Chronic toxicity 5.2.1 Ingestion No data available. 5.2.2 Inhalation No data available. 5.2.3 Dermal No data available. 5.2.4 Eye contact No data available. 5.2.5 Parenteral exposure No data available. 5.2.6 Other No data available. 5.3 Special risks 5.3.1 Pregnancy There is positive evidence of human foetal risk. A pregnant patient was treated with cisplatin (55mg), bleomycin (30mg), and etoposide (165mg) (all given daily for 3 days), 1 week prior to delivery, (27 weeks gestation), for an unknown primary cancer with metastases to the eye and liver. The mother developed profound neutropenia just prior to delivery. On the third day after birth the 1190g infant also developed leucopenia with neutropenia, 10 days after in utero exposure to the antineoplastic agents. The condition resolved after 10 days. At 1 year follow up the child was developing normally, except for moderate bilateral hearing loss. It could not be determined whether the sensorineural deafness was due to the maternal and/or neonatal gentamicin therapy or to the maternal cisplatin chemotherapy (Raffles et al, 1989). In another case a patient received a single intravenous dose of 50mg/kg cisplatin for carcinoma of the uterine cervix at 10 weeks gestation. Two weeks later, a radical hysterectomy was performed. The male foetus was morphologically normal for its developmental age (Briggs et al, 1980). A third case of cisplatin usage during pregnancy involved a 28 year old woman with advanced epithelial ovarian carcinoma. Following surgical treatment at 16 weeks gestation, the patient was treated with cisplatin, 50mg/m2 and cyclophosphamide 750mg/m2 every 21 days for seven cycles. Labour was induced at 37-38 weeks gestation leading to the birth of a healthy 3.27kg male. No abnormalities of the kidney, liver, bone-marrow, or auditory-evoked potential were found at birth, and the infant's physical and neurological growth was normal at 19 months of age (Briggs et al, 1990). Although there is evidence of human foetal risk, from the use of cisplatin in pregnant women the benefits from its use may be acceptable. 5.3.2 Breast feeding Breast feeding is not recommended due to the potential risk to the infant. A 24 year old woman with an entodermal tumour of the left ovary was treated with cisplatin, 30mg/m2 i.v. over 4 hours daily, for 5 consecutive days, with hyper-hydration. Etoposide and bleomycin were also administered during this time. Breast milk and blood collected on the third day of chemotherapy, thirty minutes before cisplatin infusion, contained platinum concentrations of 0.9mg/L and 0.8mg/L respectively. This is a milk to plasma ration of 1:1 (De Vries et al, 1989). 5.3.3 Enzyme deficiencies No data available. 5.3.4 Other No data available. 5.4 Course, prognosis, cause of death The course of cisplatin poisoning is variable However, the initial symptoms tend to be nausea and vomiting within 12-24 hours, often accompanied by diarrhoea. The more moderate symptoms are impairment of taste and speech, headache and paraesthesiae, often with hearing loss and decreased visual acuity. Rarely visual hallucinations may also be experienced. More severe effects can be expected within a week and are characterised by convulsions, twitching and dystonic movements, metabolic acidosis, coma, deafness and blindness, myelosuppression, pyrexia and acute renal failure. Toxicity is prolonged and there is a risk of secondary infection. 5.5 Diagnosis Since cisplatin is usually administered in hospital the administering clinician must monitor the patient for any signs and symptoms of toxicity. Protracted nausea and vomiting are the initial symptoms, nephrotoxicity characterised by oliguria, renal tubular acidosis and acute renal failure, is cumulative and increases with the total dose and duration of treatment. Electrolyte disturbances, particularly hypomagnesaemia and hypocalcaemia, may occur as a result of renal toxicity. Peripheral neuropathy occurs predominantly to the sensory fibres, further neurotoxicity occurs in the form of ototoxicity and visual toxicity, presenting as tinnitus, high frequency hearing loss and decreased visual acuity. Bone marrow depression may be severe, with decreased leucocyte and platelet counts Anaemia is also seen. 5.6 Systematic description of clinical effects 5.6.1 Cardiovascular Cardiovascular toxicity is rare but paroxysmal supraventricular tachycardia may occur (Fassio et al, 1986). Another report is of 4 young men (under 30 years of age) who suffered vascular ischaemic events, 2 patients had myocardial infarcts and the other 2 patients cerebrovascular accidents, days to months after receiving combination cytotoxic drug therapy including cisplatin, (Doll et al, 1986). 5.6.2 Respiratory Hyperpnoea and acute respiratory failure have been reported after overdose (Fassoulaki and Pavlou, 1989). 5.6.3 Neurological 5.6.3.1 CNS Headache, extrapyramidal disorders, impairment of taste, impairment of speech, thirst, convulsions, loss of deep tendon reflexes, gait difficulties, coma and retrobulbar neuritis have all been reported (Von Hoff et al, 1979). 5.6.3.2 Peripheral nervous system Peripheral neuropathy occurs predominantly to sensory fibres with numbness, tingling and decreased vibration sense (Mollman, 1990). 5.6.3.3 Autonomic nervous system Autonomic neuropathy occurs. 5.6.3.4 Skeletal and smooth muscle Muscle twitching and tetany has been reported due to cisplatin induced hypomagnesaemia, (Anon, 1982). 5.6.4 Gastrointestinal Nausea, vomiting and diarrhoea are the initial features of toxicity. 5.6.5 Hepatic Transient rises in AST and ALT, serum bilirubin, alkaline phosphatase, prothrombin time and partial thromboplastin time (Dorr and Fritz, 1980). 5.6.6 Urinary 5.6.6.1 Renal The kidney is the primary target organ in cisplatin toxicity. Oliguria, azotaemia, renal tubular acidosis and acute renal failure may occur, (Rozencweig et al, 1977) 5.6.6.2 Others No symptoms reported. 5.6.7 Endocrine and reproductive systems No data available. 5.6.8 Dermatological Droplet exposure of the skin to antineoplastic drugs rarely causes acute problems. Cisplatin is not absorbed through intact skin, however dermal exposure to cisplatin has resulted in skin irritation, (Khan et al, 1975) and may cause corrosive burns. 5.6.9 Eye, ears, nose, throat: local effects Eye: decreased visual acuity, papilloedema without visual disturbance, retrobulbar neuritis and cortical blindness (Kattah et al, 1987; Lindeman et al, 1990). Ears: tinnitus, high frequency hearing loss, deafness (Maiese et al, 1992). 5.6.10 Haematological Thrombocytopenia, granulocytopenia, bone marrow aplasia and bone marrow depression may occur. Anaemia has also been reported (Kumar and Dua, 1987). 5.6.11 Immunological Anaphylactic reactions may occur. 5.6.12 Metabolic 5.6.12.1 Acid-base disturbances Metabolic acidosis or respiratory alkalosis may occur. 5.6.12.2 Fluid and electrolyte disturbances Hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia and hyperuricaemia may occur in the context of renal impairment. 5.6.12.3 Others Pyrexia may occur. 5.6.13 Allergic reactions Anaphylaxis, often characterised by bronchoconstriction, facial oedema, hypotension and tachycardia may occur within minutes of administration of the drug (Von Hoff et al, 1979). 5.6.14 Other clinical effects Extravasation may occur. This is characterised by local pain, swelling and erythema around the site of injection. Localised tissue damage following extravasation may lead to tissue necrosis with skin ulcerations that are difficult to heal (Bertelli, 1995). 5.6.15 Special risks Pregnancy: there is evidence of human foetal risk (Briggs et al, 1994). The possible hazards to the foetus need to be weighed against the expected benefit to the mother in each case. Breast feeding: not recommended because of the potential risks to the baby. De Vries et al (1989) found the milk to plasma ratio to be 1:1 in a 24 year old patient. 6 TOXICOLOGICAL DATA 6.1 Human data 6.1.1 Adults No minimum lethal dose has been reported. Doses as low as 100mg/m2 in a controlled setting have been associated with minimal toxicity (Legha and Dimery, 1985). 6.1.2 Children No minimum lethal dose has been reported, although a dose as low as 100mg/m2 would be expected to cause mild toxicity. 6.2 Relevant animal data The minimum lethal dose in rhesus monkeys was 5 daily doses of 2.5mg/kg (Schaeppi et al, 1973). The minimum lethal dose for a dog was a single intravenous injection of 2.5mg/kg (Schaeppi et al, 1973) The LD50 in a rat was 12mg/kg (Keller and Aggarwal, 1983). 6.3 Relevant in vitro data In vitro cisplatin has been shown to be mutagenic in human lymphocytes, fibroblasts and lung cells (NIOSH, 1995). 7 CARCINOGENICITY The carcinogenic potential of cisplatin has not been fully evaluated. It has been shown to be carcinogenic in mice and rats. In studies in BD IX rats receiving intraperitoneal cisplatin at a dose of 1mg/kg body weight weekly for 3 weeks, 66% of the animals died within 450 days following the first application of the drug; approximately 40% of the deaths were related to malignancies (predominantly leukaemias and 1 renal fibrosarcoma) (McEvoy, 1995). 8 OTHER RELEVANT INFORMATION 8.1 Teratogenicity Cisplatin is embryotoxic and teratogenic in mice and rats (Keller and Aggarwal, 1983). 8.2 Mutagenicity In Vitro cisplatin has been shown to be mutagenic in bacteria and has produced chromosomal aberrations in animal cells in tissue culture (McEvoy, 1995). 8.3 Interactions Cisplatin is rarely used as a single agent and potential interactions with other cytotoxic agents must be carefully evaluated before initiating therapy. Bleomycin: Cisplatin can increase the pulmonary toxicity of bleomycin by decreasing its renal excretion, Cisplatin is nephrotoxic and reduces the glomerular filtration rate so that clearance of bleomycin is reduced (Yee et al, 1983; Bennett et al,1980). Aminoglycoside antibiotics: The nephrotoxic effects of cisplatin are synergistic with those of aminoglycosides and the concomitant use of these agents should be avoided. The ototoxic and magnesium losing effects of both also seem to be additive (Gonzalez-Vitale et al, 1978). Cranial irradiation: Enhanced ototoxicity has been reported in patients given cisplatin for brain tumours who had also received cranial irradiation (Reynolds, 1993). Ethacrynic acid: Animal studies indicate that ototoxicity can be markedly increased by the concurrent use of cisplatin with ethacrynic acid (McEvoy, 1995). Anticonvulsants: Phenytoin serum levels have been shown to be markedly reduced during concurrent treatment with some cytotoxic drugs and convulsions can occur if the phenytoin dosage is not raised appropriately. Similar interactions have been seen with carbamazepine and sodium valproate (Sylvester et al, 1984). 8.4 Main adverse effects Gastrointestinal: Nausea and vomiting. Renal: All patients show a transient reduction in creatinine clearance and an elevation in serum creatinine. Therefore changes in creatinine should not be considered as evidence of significant toxicity. The incidence of serious renal impairment is reduced by hydration. Hypomagnesaemia: Cisplatin alters the ability of the kidney to retain magnesium. In rare cases hypomagnesaemia may cause symptomatic muscular irritability (Stuart-Harris et al, 1980). Hypersensitivity: Occurs rarely and is characterised by the signs and symptoms of anaphylaxis (Von Hoff et al, 1976). Visual effects: Visual loss is a relatively uncommon toxic effect of cisplatin, this has been attributed to optic neuritis and cortical blindness (Kattah et al, 1987). Neuropathy: Cisplatin, particularly when given at high doses can cause a peripheral neuropathy characterised by decreased vibration sense, decreased ankle jerks and distal paraesthesiae (Mollman, 1990). Ototoxicity: Cisplatin commonly causes hearing loss, characterised by high frequency hearing deficit, tinnitus and vestibular dysfunction (Maiese et al, 1992). 8.5 Toxicodynamics Cytotoxic agents such as cisplatin affect a wide variety of cells. The major toxic effects induced by cisplatin can be classified as gastrointestinal, renal, audiological and haematological. The principal target organ for cisplatin toxicity in humans is the kidney. This is manifested by reduced renal function and deranged serum electrolytes. Doses of cisplatin sufficient to cause changes in renal function may not be associated with any histopathological alterations, although higher doses of the drug may lead to tubular necrosis, interstitial nephritis and cast formation (Anon, 1982). Cisplatin also causes nausea, vomiting and diarrhoea, bone marrow hypoplasia, changes in liver function, ototoxicity and peripheral neuropathy. 8.6 Pharmacodynamics The mechanism(s) of action of cisplatin are not fully elucidated. However cisplatin is believed to have properties similar to those of bifunctional alkylating agents. The cis configuration is necessary for the cisplatin complex to exert antineoplastic activity. Cisplatin binds to DNA and inhibits DNA synthesis, the drug produces interstrand and intrastrand crosslinks in DNA, possibly by binding at areas of specific base sequences (Reynolds, 1993; Dollery, 1991; Rozencweig et al, 1977). The relative importance of intrastrand or interstrand DNA crosslinks, in cisplatin's antineoplastic activity remains to be clearly determined. The drug is mainly cell cycle non-specific, though the effects on crosslinking are most pronounced during the S phase. Recent data suggest that mitochondrial injury in the proximal tubule is the primary event in cisplatin nephrotoxicity, this causes inhibition of ATP-dependent cellular processes including ion transport (Dollery, 1991). 8.7 Kinetics 8.7.1 Absorption by route of exposure A peak plasma concentration of 5.9 mg/L was reported at the end of a one hour infusion of 70 mg/m2 of cisplatin. (Baselt and Cravey, 1989). When cisplatin is administered by an intravenous infusion over 6 or 24 hours, plasma concentrations of total platinum peak immediately following the infusion and increase gradually during the infusion. Following 6 hour intravenous infusions of 100mg/m2 to patients with normal renal function, peak total plasma platinum and non-protein bound plasma platinum concentrations ranged between 2.5-5.3 mg/L and 0.22-0.73 mg/L, respectively (McEvoy, 1995). Following intra-arterial infusion of cisplatin, local tumour exposure to the drug is increased as compared with intravenous administration as evidenced by increased plasma platinum concentrations in local veins draining the infused region compared with systemic veins and by increased areas under the curve calculated for local versus systemic exposure. Cisplatin is rapidly and well absorbed systemically following intraperitoneal administration, resulting in 50-100% of the degree of systemic exposure compared with intravenous administration when comparable doses are given (McEvoy, 1995). 8.7.2 Distribution by route of exposure After intravenous administration cisplatin disappears from the plasma in a biphasic manner. Plasma levels of total platinum show an initial distribution with a plasma half-life of 25-49 minutes (a) followed by a second phase with a half-life of 58-73 hours (b) (De Conti et al, 1973). About 90% of the drug is protein bound within 2-4 hours of administration, and this binding is only partly reversible (Balis et al, 1983). Cisplatin is concentrated in the kidneys, liver, large and small intestines. Penetration into the central nervous system appears to be poor (Rozencweig et al, 1977). 8.7.3 Biological half-life by route of exposure Although total platinum has a bi-exponential decline with a prolonged terminal half-life of 58-73 hours, the unbound fraction which has cytotoxic activity has a much more rapid decline with a half-life of 40-48 minutes (Balis 1983). 8.7.4 Metabolism The active moiety of cisplatin is the hydrated form of the drug. The reactions shown are believed to occur in aqueous solutions. It is believed that the doubly charged diaquo species is responsible for the drug's antitumour activity. Further metabolism of these species involves interaction with and binding to cellular components including nucleic acids and proteins (De Conti et al, 1973).8.7.5 Elimination by route of exposure Cisplatin is mainly excreted by glomerular filtration in the urine. Up to 43% of a dose has been reported to be excreted in urine over 50 days (Reynolds, 1990). Initially cisplatin is excreted unchanged and later most of the drug is excreted as biotransformation products. However, excretion is incomplete and platinum may be detected in tissue for several months after cessation of therapy. 9 MANAGEMENT 9.1 First-aid measures and management procedures There is no specific antidote, treatment is symptomatic and supportive. Initially hydration is the most important aspect of treatment, volumes of 3-4 litres per day have been used in adults, whilst children have received 3L/m2/day (Haupt et al, 1989), to reduce the risk of nephrotoxicity. Severe nausea and vomiting may be managed with antiemetics (e.g. ondansetron, metoclopramide or buspirone). Patients should be monitored closely for signs and symptoms of toxicity especially ototoxicity, and changes in cardiac, liver, renal and neurological function. 9.2 Decontamination Remove and discard any contaminated clothing, laundering of non-disposable materials has not been demonstrated to remove cytotoxic contaminants. Cytotoxic waste may be placed in a thick sealable polythene bag, then within a second bag and sealed. The bags must then be labelled and destroyed appropriately. Treatment for dermal exposure to cisplatin involves washing the exposed area thoroughly with soap and water. If pain and irritation persists, treat symptomatically and supportively. Exposed eyes should be irrigated with copious amounts of water or saline for at least 15 minutes. The eye should then be stained with fluorescein. If irritation, pain, swelling, lacrimation or photophobia persists after 15 minutes of irrigation consult an ophthalmologist. Cisplatin is not thought to be absorbed through the gastrointestinal tract, although preliminary reports suggest that this may occur in rats and mice. In case of ingestion empty the stomach within 2 hours of ingestion, there is no evidence that activated charcoal will bind cisplatin. 9.3 General principles Treatment is symptomatic and supportive. There is no specific antidote. Patients should be monitored closely for signs and symptoms of toxicity, especially ototoxicity, cardiac, liver, renal and neurological function. Since cisplatin is not available in an oral dosage form, gut decontamination is not usually required. Initially hydration is the most important aspect of treatment. Intravenous administration of fluids (usually normal saline) in volumes of 3-4 litres per day has been used to reduce the risk of nephrotoxicity. In severe poisoning the volume of fluid administered may be increased to 5-6 litres daily. Severe nausea and vomiting may be managed with antiemetics, either metoclopramide or buspirone. Convulsions may be controlled by diazepam. If convulsions cannot be controlled or recur, administer phenytoin or phenobarbitone. Severe myelosuppression may occur and peripheral blood counts should be monitored weekly. The lowest counts may be seen at about 2-3 weeks post-exposure. Monitor patient for bleeding episodes and infection. Transfusions of packed red cells and platelets may be required if severe bleeding occurs. If infection occurs, culture the organism and begin appropriate antimicrobial therapy. Monitor and correct electrolyte disturbances, including serum creatinine and creatinine clearance or glomerular filtration rate as appropriate. Renal function should be closely followed. Monitor the ECG and perform liver function tests. Sensory potentials, visual evoked potential and brainstem auditory evoked potentials may provide early evidence of central nervous system toxicity. 9.4 Life supportive procedures and symptomatic/specific treatment The principal target organ for cisplatin toxicity is the kidney, therefore vigorous rehydration is initially the most important requirement, following patient stabilisation. Monitor and correct electrolytes. Monitor audiological, cardiac, liver, and neurological function. Management of cisplatin extravasation is based on clinical experience and published case reports. Cases of extravasation should be prevented through careful administration of vesicant drugs such as cisplatin. Check frequently for venous blood return and for signs of redness and swelling during administration. If extravasation occurs, stop the infusion immediately and attempt to aspirate some of the extravasated fluid before withdrawing the needle. Both topical cooling and sodium thiosulphate have been advocated as possible antidotes after extravasation of cisplatin. Isotonic sodium thiosulphate (0.17mol/L) was administered by deep intramuscular injection around a chlomethine injection site, a vesicant drug, and an ice pack placed on the area for 12 hours. This provided complete protection from the expected tissue necrosis (Bertelli, 1995). 9.5 Elimination Haemodialysis was ineffective in preventing the development of cisplatin toxicity when started 4 hours post-overdose possibly due to rapid protein binding (Brivet et al, 1986). It will be indicated if renal failure occurs. It has been suggested that removal of plasma proteins by plasma exchange might be an effective method of reducing the body burden following overdose (Poisindex, 1995). 9.6 Antidote treatment There is no specific antidote for cisplatin and treatment is generally symptomatic and supportive. 9.7 Clinical chemistry/toxicological analysis 9.7.1 Biomedical analysis Monitor electrolytes, blood urea nitrogen, serum creatinine, creatinine clearance and peripheral blood counts. 9.7.2 Toxicological analysis Unlikely to be required. 9.7.3 Other investigations Monitor the ECG and liver function tests. Sensory potentials, visual evoked potentials and brainstem auditory evoked potentials may provide early evidence of central nervous system toxicity. 9.8 Management discussion: alternatives and controversies Fosfomycin, a phosphonic acid antibiotic produced from streptomyces species is being investigated for efficacy in prevention of cisplatin induced ototoxicity, renal toxicity, and haemopoietic toxicity. Fosfomycin has been reported in animals and humans to be effective in inhibition of nephrotoxicity of aminoglycosides when coadministered. Supplemental treatment with fosfomycin (2 grams twice daily from the first to the fourth day of each cycle) was shown to reduce cisplatin- induced nephrotoxicity in one study. Additional studies are needed to demonstrate efficacy for the use of fosfomycin in cisplatin overdose (Umeki et al, 1988). Sodium thiosulphate may protect against cisplatin induced neurotoxicity. In vitro and in vivo demonstrations have shown prevention of certain toxic effects of cisplatin by several thiol containing compounds. Twenty four patients were studied to determine if sodium thiosulphate injection would permit larger cisplatin doses to be administered. A fixed dose of 9.9g/m2 of thiosulphate was given intravenously over three hours concurrently with escalating doses of cisplatin. Cisplatin was administered over the last two hours of the thiosulphate infusion. Using this technique, it was possible to escalate the cisplatin dose to 225mg/m2 before dose limiting toxicities were encountered. Sodium thiosulphate was also shown to reduce the side effects of cisplatin to a minimal level without impairing its antitumour activity in a study of 61 patients (Pfeifle et al, 1985). Additional studies are needed to determine if sodium thiosulphate administered after an overdose will prevent cisplatin nephrotoxicity (Pfeifle et al, 1985). Supplemental treatment with steroids, methylprednisolone (250mg) or hydrocortisone (300mg) once a day on the first day of each cycle was effective in reducing cisplatin-induced nephrotoxicity in one study. Additional studies are required to demonstrate efficacy for the use of these steroids in cisplatin overdose (Umeki et al, 1988). A combination of verapamil (80 mg orally three times daily) and cimetidine (200 mg orally three times daily plus an additional intravenous dose of 400 mg on days 1-5, 2 hours before every cisplatin infusion) beginning one day before the cisplatin dose, was found to be protective for cisplatin-induced nephrotoxicity. Additional studies are needed to demonstrate efficacy for the use of verapamil and cimetidine in cisplatin overdose (Poisindex, 1995). Cisplatin exerts its antitumour effects through positively charged electrophilic alkyl groups which prevent or disrupt cell division. It is these groups, however that are also responsible for the adverse effects of cisplatin. These adverse effects can be reduced by providing excess neutrophilic sites such as free sulphydryl groups through the use of so called chemoprotective agents. However, provision of excess neutrophilic sites must be selective otherwise antitumour activity will also be reduced. Chemoprotective agents which have been investigated include amifostine (WR 2721), diethyldithiocarbamate (DDTC), ORG 2766 (Gandara et al, 1991; Schuchter et al, 1992) and glutathione (Bohm et al, 1991). In phase 1 trials of amifostine in combination with mannitol diuresis. Transient nephrotoxicity occurred in 9 of 30 (27%) patients treated with cisplatin 150mg/m2 and in 7% treated with 120mg/m2. Bone marrow suppression was mild and infrequent. Mild to moderate neuropathies occurred in 26% of patients on a mean cumulative cisplatin dose of 725mg/m2 (Glover et al, 1989). Amifostine is now available from Schering-Plough and is licensed for use in patients with advanced ovarian cancer to reduce the neuropenia related risk of infection due to cisplatin or cyclophosphamide therapy. The efficacy of amifostine in overdose has not been evaluated. Diethyldithiocarbamate (DDTC) has been used in an investigational phase 1 clinical trial to demonstrate the feasibility of using DDTC for renal protection at standard cisplatin doses of 50-120 mg/m2. A further study reported preliminary observations of plasma platinum and DDTC pharmacokinetics for high-dose cisplatin (200 mg/m2/cycle). A dose of 4g/m2 was administered by intravenous infusion over 1.5-3.5 hours beginning 45 minutes after completion of the cisplatin infusion. Predicted plasma DDTC levels for chemoprotective effect (greater than 400 micromoles) were achieved with this dose and schedule. However the DDTC infusion resulted in side effects including flushing, chest discomfort, and anxiety. Additional studies are needed before DDTC can be recommended for the treatment of cisplatin overdose (Poisindex, 1995). An ACTH (4-9) analogue, ORG 2766, is being investigated as a means of preventing cisplatin neurotoxicity. One study found that 0.25mg (low dose) or 1mg/m2 (high dose) of ORG 2766 administered subcutaneously before and after treatment, with cisplatin and cyclophosphamide could attenuate or prevent cisplatin neuropathy (van der Hoop et al, 1990). Further studies are required before this treatment can be recommended in humans following overdose. 10 LABORATORY INVESTIGATIONS 10.1 Sample collection Flameless atomic absorption spectrometry has been used to determine free or total platinum in plasma. (Baselt and Cravey 1989). Blood samples may be collected in heparinized or acid citrate dextrose tubes, spun in a clinical centrifuge within 10 minutes of collection and immediately separated as plasma samples for analysis (Chu et al, 1993). 10.2 Transport of laboratory samples and specimens 10.3 Interpretation of toxicological analyses 10.4 Biomedical investigations and their interpretation Peripheral blood counts should be monitored weekly, the lowest counts may be seen at about 2-3 weeks post-exposure. Monitor and correct electrolytes including serum creatinine and creatinine clearance, as appropriate. Liver function tests should be performed regularly to reduce the risk of hepatotoxicity. 11 ILLUSTRATIVE CASES 11.1 Case reports from the literature 1) A 41 year old female patient was administered a double dose of cisplatin (200mg/m2) on the 5th day of her first course of polychemotherapy for treatment of stage III primary ovarian carcinoma. Other treatment included doxorubicin (25mg/m2) and teniposide (35mg/m2) on day 1, cyclophosphamide (200mg/m2) and 5-fluorouracil (350mg/m2) on days 2-4. On day 5 cisplatin 100 mg/m2 was to be administered, however two doses were inadvertently administered. Nausea and vomiting was reported one hour after the second dose of 100mg/m2, treatment with intravenous hydration of 25% mannitol and 5% dextrose was initiated immediately. The patient complained of headache, a metallic taste, nausea and thirst. Haemodialysis was begun four hours after the end of the second dose cisplatin. Five days post intoxication metabolic acidosis, acute renal failure, and febrile bone marrow aplasia was reported. Treatment consisted of antibiotics, haemodialysis and transfusions. Bone marrow depression and acute renal failure resolved, a second course of chemotherapy two months later with cisplatin 50mg/m2 produced myelosuppression without renal failure (Brivet et al, 1986). 2) A 36 year old male with testicular choriocarcinoma developed oliguric renal failure, febrile myelosuppression, decreased hearing, thick speech, impairment of taste, and numbness of the hands and feet one week after a cisplatin overdose. Rather than receiving 40mg/m2/day divided into three equal eight hour infusions, the patient received a continuous infusion of 40 mg/m2 every eight hours for 4 days, a total dose of 480 mg/m2. The patient required haemodialysis for 1 month until his serum creatinine fell below 8 mg/100ml. On follow up eighteen months later dysarthria, taste disturbance and left hand weakness had resolved, serum creatinine had stabilized at 3.5mg/100ml and his creatinine clearance was 26 ml/minute, however he still required hearing aids (Schiller et al, 1989). 3) A 6 month old infant with a localized, unresectable embryonal rhabdomyosarcoma of the shoulder received an overdose of cisplatin, 90mg/m2 of cisplatin daily for 5 days in combination with standard doses of VP-16 (100mg/m2 for 5 days). The cisplatin was diluted in 250ml/m2 of 3% hypertonic saline and administered as a one hour infusion with vigorous hydration of 3L/m2/day of normal saline. Vomiting began on day 2 and continued for 7 days, diarrhoea was also reported, total parenteral nutrition was required for 28 days. Severe haematological toxicity occurred, white blood cells dropped to 800/mmc in 10 days with PMNs below 500/mmc from the 5th to the 17th day from the end of the cycle. Pyrexia (39°C) developed on day 10 and resolved 24 hours later following antimicrobial therapy. A nadir in platelet count of 5000/mmc was observed on day 13. Treatment involved transfusion of four units of platelets and haemoglobin was maintained over 10g/L with three transfusions of packed red cells. Renal function was monitored daily, no elevation of serum creatinine, BUN or uric acid was observed, but by the 8th day after treatment, moderate hyperchloraemic acidosis developed as a result of severe impairment in the tubular function with urinary bicarbonate losses up to 10 times the normal values for the patient's age. The impairment continued for three weeks and then gradually resolved completely. Daily EEGs and peripheral nerve function normal (Haupt et al, 1989). 11.2 Internally extracted data on cases No data available. 12 ADDITIONAL INFORMATION 12.1 Specific preventive measures None. 12.2 Other None. Authors Robie Kamanyire National Poisons Information Service (London Centre) Medical Toxicology Unit Guy's & St Thomas' Hospital Trust Avonley Road London SE14 5ER UK This monograph was produced by the staff of the London Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. June 1995 REFERENCES Anon. (1982) Cisplatin. Lancet 1:374-375 Balis FM, Holcenberg JS, Bleyer WA. (1983) Clinical pharmacokinetics of widely used anticancer drugs. Clin Pharmacokin 8 (3): 202-32 Baselt RC and Cravey RH. 1989 Disposition of toxic drugs and chemicals in man 3rd ed. Year Book Medical Publishers Bennett WM, Pastore L and Houghton DC. (1980) Fatal pulmonary toxicity in cis-platin induced renal failure. 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