Incidences of adverse reactions reported hereunder are based on cumulative data obtained in a large group of patients with various pretreatment prognostic features.
Haematological toxicity:
Myelosuppression is the dose-limiting toxicity of carboplatin. At maximum tolerated dosages of carboplatin administered as a single agent, thrombocytopenia, with nadir platelet counts of less than 50 x 109/L, occurs in about a quarter of the patients.
The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start of therapy. Leukopenia has also occurred in approximately 14% of patients but its recovery from the day of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of therapy.
Neutropenia with granulocyte counts below 1 x 109/L occurs in approximately one fifth of patients. Anaemia with haemoglobin values below 11g/dL has been observed in more than two-thirds of patients with normal base-line values. Myelosuppression may be more severe and prolonged in patients with impaired renal function, extensive prior treatment, poor performance status and age above 65.
Myelosuppression is also worsened by therapy combining carboplatin with other compounds that are myelosuppressive. Myelosuppression is usually reversible and not cumulative when carboplatin is used as a single agent and at the recommended dosages and frequencies of administration.
Infectious complications have occasionally been reported. Haemorrhagic complications, usually minor, have also been reported.
Nephrotoxicity:
Renal toxicity is usually not dose-limiting in patients receiving carboplatin, nor does it require preventive measures such as high volume fluid hydration or forced diuresis. Nevertheless, increasing blood urea or serum creatinine levels can occur.
Renal function impairment, as defined by a decrease in the creatinine clearance below 60 ml/min, may also be observed. The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment.
It is not clear whether an appropriate hydration programme might overcome such an effect, but dosage reduction or discontinuation of therapy is required in the presence of severe alteration of renal function tests. Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) have been reported after treatment with carboplatin but have not been reported to be severe enough to cause the appearance of clinical signs or symptoms.
Cases of hyponatraemia have been reported. Haemolytic uraemic syndrome has been reported rarely.
Gastrointestinal toxicity:
Nausea without vomiting occurs in about 15% of patients receiving carboplatin; vomiting has been reported in over half of the patients and about one-fifth of these suffer severe emesis. Nausea and vomiting usually disappear within 24 hours after treatment and are usually responsive to (and may be prevented by) anti-emetic medication.
A fifth of patients experience no nausea or vomiting. frequency unknown: pancreatitis Cases of anorexia have been reported. , erythematous rash, fever with no apparent cause or pruritus. Rarely, anaphylaxis, angio-oedema and anaphylactoid reactions, including bronchospasm, urticaria and facial oedema have occurred.
) Ototoxicity: Subclinical decrease in hearing acuity, consisting of high-frequency (4000- 8000 Hz) hearing loss determined by audiogram, has been reported in 15% of the patients treated with carboplatin. However, only 1% of patients present with clinical symptoms, manifested in the majority of cases by tinnitus.
In patients who have been previously treated with cisplatin and have developed hearing loss related to such treatment, the hearing impairment may persist or worsen. At higher than recommended doses in combination with other ototoxic agents, clinically significant hearing loss has been reported to occur in paediatric patients when carboplatin solution was administered.
Neurotoxicity:
The incidence of peripheral neuropathies after treatment with carboplatin is 4%. In the majority of the patients neurotoxicity is limited to paraesthesia and decreased deep tendon reflexes. The frequency and intensity of this side effect increases in elderly patients and those previously treated with cisplatin.
Paraesthesia present before commencing carboplatin therapy, particularly if related to prior cisplatin treatment, may persist or worsen during treatment with carboplatin.
Ocular toxicity:
Transient visual disturbances, sometimes including transient sight loss, have been reported rarely with platinum therapy. This is usually associated with high dose therapy in renally impaired patients.
Nervous system disorders frequency unknown:
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Metabolism and Nutrition Disorders : frequency unknown: Tumor lysis syndrome Infection and infestation frequency unknown: pneumonia Other: Abnormalities of liver function tests (usually mild to moderate) have been reported with carboplatin in about one-third of the patients with normal baseline values.
The alkaline phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin. The majority of these abnormalities regress spontaneously during the course of treatment. Infrequent events consisting of taste alteration, asthenia, alopecia, fever and chills without evidence of infection have occurred.