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Cisplatin is a highly toxic drug with a relatively narrow therapeutic index, and a therapeutic effect is unlikely to occur without some evidence of toxicity. Cisplatin should be administered only under constant supervision by physicians experienced in therapy with cytotoxic agents and only when potential benefits of cisplatin therapy outweigh the possible risks. Appropriate facilities should be available for adequate management of complications should they arise.
To minimise the risk of nephrotoxicity, hydrate before, during and after therapy (see Dosage & Administration). Prior to initial therapy, then before subsequent doses, the following parameters should be monitored: renal function including Glomerular Filtration Rate (GFR), Blood Urea Nitrogen (BUN), serum creatinine and creatinine clearance; electrolytes (magnesium, sodium, potassium and calcium) to detect hypomagnesaemia or hypocalcaemia; auditory function; red blood cells, white blood cells and platelets; liver function and neurological status.
Myelosuppression: This may occur in patients treated with cisplatin. Haematological toxicity is dose-related and cumulative. The lowest levels of circulating platelets and leucocytes generally occur between 18-23 days (range 7.3-45) with most patients recovering after 39 days (range 13-62). Leucopenia and thrombocytopenia are more pronounced at doses greater than 50 mg/m2.
Peripheral blood counts should be monitored frequently in patients receiving cisplatin. Although the haematologic toxicity is usually moderate and reversible, severe thrombocytopenia and leucopenia may occur. In patients who develop thrombocytopenia special precautions are recommended: care in performing invasive procedures; search for signs of bleeding or bruising; test of urine, stools and emesis for occult blood; avoiding aspirin and other NSAIDs. Patients who develop leucopenia should be observed carefully for signs of infection and might require antibiotic support and blood product transfusions.
Subsequent courses of cisplatin should not be instituted until platelets are present at levels greater than 100,000/mm3 and white cells greater than 4,000/mm3.
Anaemia: Anaemia (decrease of greater than 2g/dL haemoglobin) occurs in a significant number of patients, usually after several courses of treatment. Anaemia occurs at approximately the same frequency but generally with a later onset than leucopenia and thrombocytopenia. Transfusions of packed red cells may be necessary in severe cases.
Rarely, the drug has caused haemolytic anaemia; Coombs-positive results have been reported in a few of these cases. Further courses with cisplatin in sensitised individuals may cause increased haemolysis.
A high incidence of severe anaemia requiring transfusion of packed red cells has been observed in patients receiving combination chemotherapy including cisplatin.
Nausea and Vomiting: Marked nausea and vomiting occur in almost all patients treated with cisplatin and are occasionally so severe that dosage reduction or discontinuance of treatment is necessary.
Ototoxicity: Ototoxicity is cumulative and occurs mainly with high dose regimes. Tinnitus or occasional decreased ability to hear normal conversation are indications of ototoxicity, which have been frequently observed. Tinnitus is usually transient lasting from a few hours to a week after cessation of therapy. Hearing loss is usually unilateral or bilateral and occurs in the 4000 to 8000 Hz range. Frequency and severity of these hearing disorders increases with repeated doses and severe impairment may not be reversible.
Audiometric testing should be performed, if possible prior to initiation of therapy and at regular intervals thereafter, particularly if the clinical symptoms of tinnitus or hearing impairment occur. Radiotherapy may enhance ototoxicity. Clinically important deterioration of auditive function may require dosage modifications or discontinuation of therapy.
Hypomagnesaemia and Hypocalcaemia: Hypomagnesaemia occurs quite frequently with cisplatin administration, while hypocalcaemia occurs less frequently. The loss of magnesium seems to be associated with renal tubular damage which prevents resorption of this cation. Where both electrolytes are deficient, tetany may result. It does not appear to be dose related. Monitoring of electrolytes is necessary.
Neurotoxicity: Cisplatin is known to induce neurotoxicity; therefore, neurologic examination is warranted in patients receiving a cisplatin-containing treatment. Peripheral neuropathy, postural hypotension, myasthenic syndromes, seizures and visual loss may occur especially after prolonged cisplatin treatment. Since neurotoxicity may result in irreversible damage cessation of cisplatin is recommended if these symptoms occur.
Anaphylaxis: Occasionally reactions secondary to cisplatin therapy have been reported in patients who were previously exposed to cisplatin. Patients with a prior history or family history of atopy are at particular risk. Facial oedema, wheezing, tachycardia, hypotension and skin rashes of urticarial non-specific maculopapular type can occur within a few minutes of administration. Serious reactions seem to be controlled by IV adrenaline, corticosteroids or antihistamines.
Patients receiving cisplatin should be observed carefully for possible anaphylactic like reactions and the necessary supportive equipment and medication should be readily available to treat such reactions.
Cardiovascular Toxicity: Cisplatin has been found to be associated with cardiovascular toxicity (see Adverse Reactions). Patients may experience clinically heterogeneous venous thromboembolic events, myocardial infarction, cerebrovascular accidents, thrombotic microangiopathy and cerebral arteritis. Cases of pulmonary embolism (including fatalities) have been reported (see Adverse Reactions).
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cisplatin, may result in serious or fatal infections. Extreme caution should be used where patients have recently been exposed to infections, particularly chicken pox and herpes zoster. Live vaccines should not be used in patients undergoing cisplatin therapy. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Dental: The bone marrow depressant effects of cisplatin may result in an increased incidence of microbial infection, delayed healing and gingival bleeding. Dental work should be avoided during cisplatin therapy.
Other: As patients undergoing treatment with cisplatin are at an increased risk of bleeding, bruising and infection, it is recommended that extreme care be used when performing necessary invasive procedures.
Alcohol and aspirin should be avoided because of the risk of gastrointestinal bleeding.
Effects on Laboratory Tests: No data available.
Effects on ability to drive and use machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in hepatic impairment: Liver function should be monitored periodically.
Use in renal impairment: Cisplatin is contraindicated in patients with severe renal impairment (see Contraindications).
Cumulative and dose-related renal insufficiency is the major dose-limiting toxicity of cisplatin. The most commonly observed changes are a fall in GFR reflected by a rise in serum creatinine and a reduction in effective renal plasma flow.
Pre and post treatment hydration may reduce nephrotoxicity (see Dosage & Administration).
Renal function must return to normal before further doses are given (see Dosage & Administration).
Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs (see Interactions).
Use in Children: Cisplatin can also be used in children. Cases of delayed-onset hearing loss have been reported in the paediatric population. Long term follow-up in this population is recommended.
Use in the Elderly: No data available.
