INFORMATION FOR HEALTH PROFESSIONALS
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Injection: a clear, colourless solution contained in a glass vial with butylrubber stopper, and containing 10 mg/mL carboplatin. pH 2.9 - 3.3.
Carboplatin is a platinum co-ordinated complex with biochemical properties similar to that of cisplatin. The proposed mechanism of action is DNA cross-linkage. The effect is cell-cycle non-specific.
After intravenous administration plasma concentration of intact carboplatin declines in a biphasic manner with an initial half-life (alpha) of 1 to 2 hours and a post distribution half-life (beta) of 3 to 6 hours. The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours respectively.
Carboplatin is not significantly bound to plasma proteins. However platinum from carboplatin becomes irreversibly bound to plasma proteins with 87% of the platinum being bound within 24 hours of administration. This is then slowly eliminated (half-life 5 days). A linear relationship exists between dose and plasma concentrations of total and free ultrafiltrable platinum.
Carboplatin is excreted primarily in the urine with 65% of the dose excreted unchanged in the urine after 12 hours and approximately 70% within 24 hours. In patients with impaired renal function (creatinine clearance less than 60 mL/min) carboplatin excretion decreases as creatinine clearance decreases.
Carboplatin is indicated for palliative treatment of patients with advanced or recurrent ovarian carcinoma, including patients previously treated with cisplatin.
Carboplatin also may be used for the treatment of small cell lung carcinoma, and carcinoma of the head and neck.
Carboplatin injection 10 mg/mL is intended for intravenous use. The recommended starting dose for previously untreated patients with normal kidney function is 400 mg/m² as a single i.v. dose, usually administered as a short term (15-60 min) infusion, once every four weeks. However it may be necessary to delay the repeat dose when myelosuppression is severe (platelets less than 50,000 cells/mm³, neutrophils less than 2,000 cells/mm³) until bone marrow has sufficiently recovered.
After the first course, dosage may be adjusted according to the patient's tolerance.
Reduction of the initial dose to 300-320 mg/m² is recommended with concomitant myelosuppressive therapy, or other risk factors (see Warnings and Precautions).
Aluminium can react with carboplatin causing precipitate formation and loss of potency. Do not use needles or i.v. administration sets containing aluminium parts that may come in contact with carboplatin for the preparation or administration of the medicine.
Patients with a creatinine clearance less than 60 mL/min are at increased risk of severe myelosuppression. Recommended starting doses for these patients are creatinine clearance 41-59 mL/min, 250 mg/m² and creatinine clearance 20-40 mL/min, 200 mg/m². Insufficient data are available for patients with a creatinine clearance below 20 mL/min, and treatment is not recommended in these cases.
Needles, syringes, or sets with aluminium components should not be employed in preparation or administration of carboplatin solution.
The contents of the vial should be discarded 8 hours after opening as the formulation contains no preservative.
Preparation of carboplatin should be done in a vertical laminar flow hood. Personnel preparing carboplatin should wear PVC gloves, safety glasses, disposable gowns and masks.
All needles, syringes, vials and other materials which have come in contact with carboplatin should be segregated and incinerated at 1,000°C or more. (NB: sealed containers may explode). Proper precautions should be taken in packaging these materials for transport.
Personnel regularly involved in the preparation and handling of carboplatin should have bi-annual blood examinations.
Carboplatin is contraindicated in patients with a history of severe allergic reactions to platinum-containing compounds; in patients with severe myelosuppression; also in patients with severe renal impairment (creatinine clearance less than 20 mL/min).
Myelosuppression, especially thrombocytopenia and leucopenia, is dose-dependent and related to renal function.
Peripheral blood counts should be monitored frequently during and after treatment, and renal function should be assessed. Median nadir occurs at day 21 in patients receiving single agent carboplatin. In general single intermittent course should not be repeated until leucocyte, neutrophil and platelet counts recover. Since anaemia is cumulative, transfusions may be needed during treatment.
Dose reductions are generally necessary in patients with concomitant treatment with other myelosuppressive agents; patients with inadequate bone marrow reserves due to previous treatments or bone metastases; patients with impaired renal function; patients with poor performance status and older patients.
Carboplatin dosage should be reduced in patients with impaired renal function (creatinine clearance less than 60 mL/min). Creatinine clearance has been the most sensitive measure of kidney function in carboplatin patients and it appears to be the most useful test for correlating carboplatin clearance and bone marrow suppression.
Carboplatin has limited nephrotoxic and ototoxic potential, but concomitant treatment with aminoglycosides or other nephrotoxic or ototoxic agents may result in an increased risk for renal or auditory toxicity.
Allergic reactions to carboplatin have been reported and may occur within minutes of administration; manage with appropriate supportive therapy.
Emetic potential of carboplatin is significantly less than that of cisplatin. Both nausea and vomiting usually cease within 24 hours of treatment and the incidence and intensity of emesis have been reduced by premedication with antiemetics. The following schedules of carboplatin may reduce emesis: lengthening the duration of single i.v. administration to 24 hours or dividing the total dose over five consecutive days.
Peripheral neurotoxicity is infrequent, however, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Although the overall incidence of peripheral neurologic side-effects induced by carboplatin is low, prolonged treatment, particularly in cisplatin pre-treated patients, may result in cumulative neurotoxicity.
Aluminium can react with carboplatin causing precipitate formation and loss of potency. Do not use needles or i.v. administration sets containing aluminium parts that may come in contact with carboplatin for the preparation or administration of the medicine.
High dosages of carboplatin (more than four times the recommended dose) have resulted in abnormalities of liver function tests, which have generally been mild and reversible in about 50% of the cases; however, the role of metastatic tumour in the liver may complicate the assessment in many patients.
Carboplatin has demonstrated embryotoxic and teratogenic effects in animals. Carboplatin has been shown to have a mutagenic potential in vitro and in vivo. Therefore, the use of carboplatin should be avoided if possible during pregnancy.
Women of childbearing potential should use adequate contraception.
It is not known whether carboplatin is excreted in human milk. It is recommended that lactation is discontinued during carboplatin treatment.
Myelosuppression is the major dose-limiting toxicity of carboplatin. Thrombocytopenia (platelets 50,000/mm³) is seen in most of the patients, with a nadir at about 3 weeks and full recovery at 4-5 weeks. Leucopenia is usually less pronounced, with a nadir at about 3 weeks and a somewhat slower recovery at 5 weeks. Anaemia is commonly seen, but is usually not of a severe nature.
Bone marrow depression is more severe in patients with impaired renal function, patients with an inadequate bone marrow reserve, or patients with poor performance status. Haematologic effects although usually reversible, have resulted in infectious or haemorrhagic complications.
Nausea and vomiting frequently occurs but is usually classified as mild to moderate. Approximately 20% may experience severe emesis. Diarrhoea and constipation have also been reported.
Peripheral neuropathies have been observed in 5% of the patients, mild paresthesias occurring most frequently. The incidence and severity may be increased in patients previously treated with cisplatin.
Clinical symptoms of ototoxicity, mostly tinnitus, occur in 1% of patients. Subclinical decreases in hearing acuity consisting of high frequency hearing loss as determined by audiogram have been reported in some 15% of patients.
Abnormal renal function tests such as decreased creatinine clearance, increased blood urea nitrogen, serum creatinine and urate have been reported during treatment.
Carboplatin treatment may result in a decrease in serum electrolytes, including sodium, potassium, magnesium and calcium, but these electrolyte abnormalities are rarely associated with clinical symptoms.
Mild to moderate reversible abnormalities of liver function tests have been reported in up to a third of patients. The majority of the abnormalities regress spontaneously during the course of treatment.
Hypersensitivity to carboplatin has been reported in 2% of patients. These allergic reactions have been similar in nature and severity to those reported with other platinum-containing compounds, i.e. rash, urticaria, erythema and pruritis.
Alopecia, mucositis, headache, pain and asthenia have been reported rarely. Fever and chills without evidence of infection or allergy have also been reported.
Myelosuppression by carboplatin may be more severe with prior or concomitant treatment with other myelosuppressive agents. Concomitant treatment with other nephrotoxic or ototoxic agents (eg aminoglycoside antibiotics) increases the risk of renal or auditory toxicity during carboplatin treatment.
There is no known antidote to carboplatin overdosage. The anticipated complications of overdosage would be related to myelosuppression, hepatic toxicity and/or renal toxicity.
Unopened vials stored at room temperature have a shelf life of 1 year. Protect from light.
Use within 8 hours after opening.
Prescription Medicine
Carboplatin Injection 10 mg/mL: vials containing 50 mg/5mL, 150 mg/15mL, 500 mg/50mL.
Carboplatin (cisdiammine (1,1-cyclo-butanedicarboxylato) platinum) is a white crystalline substance freely soluble in water, MW 371 daltons.
Manufacturer:
PHARMACHEMIE B.V
PO Box 552
2003 RN Haarlem
The Netherlands
Distributor:
ASTA Medica Australasia Pty Limited
c/- N Z M S Limited
PO Box 24-138, Royal Oak
AUCKLAND
2 October 1991