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150 mg / 15 ml
450 mg / 45 ml
Carboplatin Injection does not contain any antimicrobial preservative; it is intended for single-dose administration only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Administration: This preparation is intended for intravenous use only, usually by an infusion lasting 15 minutes or longer. It may be given to outpatients since hydration is not required. Aluminium reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin. Therapy should not be repeated until four weeks after the previous carboplatin course. and/or until the neutrophil count is at least 2000 cells/mm3 and the platelet count is at least 100.000 cells/ mm3. Therapy with carboplatin should be discontinued in the case of an unresponsive tumour, progressive disease and/or occurrence of not tolerable side effects. Reduction of the initial dosage by 20 – 25% is recommended for those patients who present with risk factors such as prior myelosuppressive treatment and low performance status (ECOG-Zubrod 2 – 4 or Karnofsky below 80). Determination of the haematological nadir by weekly blood counts during the initial courses of treatment with carboplatin is recommended for future dosage adjustment.
Advanced ovarian carcinoma: Initial Treatment: In patients with advanced ovarian carcinoma, carboplatin administered in combination therapy as established by specialists, is recommended at a dosage of 300 mg/m2 I.V. on day 1 every 4 weeks for six cycles.
Secondary Treatment: Carboplatin, as monotherapy, has been shown to be effective in patients with recurrent ovarian carcinoma. The recommended dosage is 360 mg/m2 I.V. on day 1 every 4 weeks.
Metastatic Small Cell Carcinoma of the Lung: The recommended dosage is 400 mg/m2 as a single I.V. dose administered by a short-term (15 – 60 minutes) infusion. Therapy should not be repeated until 4 weeks after the previous carboplatin course. The optimal use in combination with other myelosuppressive agents requires dosage adjustments according to the regimen and schedule to be adopted. Impaired renal function. Patients with creatinine clearance values of less than 60 ml/min are at greater risk of severe myelosuppression. The optimal use of carboplatin in patients presenting with renal impairment requires adequate dosage adjustment and frequent monitoring of haematological nadirs, electrolytes and renal function. The onset of severe leucopenia, neutropenia or thrombocytopenia may be controlled using the following posology:
-250 mg/m² i.v. on day 1, in patients with creatinine clearance base values from 41 – 59 ml/min. -200 mg/m² i .v. on day 1, in patients with creatinine clearance base values from 21 – 40 ml/min. These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance, based on the degree of bone marrow suppression. In general, intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2,000 cells/mm3 and platelet count is at least 100,000 cells/mm3. Carboplatin should not be administered to patients with a creatinine clearance ≤20 ml/min.
Dose recommendations according to AUC: Alternatively, the initial dose can be calculated using the Calvert formula. This is based on renal function (glomerular filtration rate [GFR]). Thereby, the risk of underdosing or overdosing due to individual differences in renal function is reduced. Calvert formula: total dose (mg) = (target AUC*) x (GFR + 25).
Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.
- the target AUC is 5-7 mg/ml min, when the planned chemotherapy is a single agent carbopatin, and no prior therapy.
- the target AUC is 4-6 mg/ml min, when the planned chemotherapy is a single agent carbopatin, and there was a prior therapy.
- the target AUC is 4-6 mg/ml min, when the planned chemotherapy is carboplatin plus cyclophosphamidele agent carbopatin, and there was no prior therapy.
The Calvert formula should not be used in heavily pre-treated patients who have already received one of the following regimens:
– mitomycin C
– doxorubicin/cyclophosphamide/cisplatin combination chemotherapy
– combination therapy including 5 or more cytostatic agents
– radiation therapy ≥5000 rad focused on a field of 20 x20 cm or more than one field.
Decreased platelet and neutrophil counts. For patients who experience no hematologic toxicity (i.e., platelet and neutrophil counts remain above 100,000 and 2,000/mm3 respectively) with the previous dose, dosage of carboplatin in single or combination (e.g., cyclophosphamide) therapy may be increased by 25%. For patients who experience only mild to moderate hematologic toxicity (i.e., platelet or neutrophil counts of 50,000-100,000 or 500-2,000/mm3, respectively) with the previous dose, dosage adjustment is not necessary in single agent or combination regimens. For patients who experience moderate to severe hematologic toxicity (e.g., platelet or neutrophil counts lower than 50,000 or 500/mm3, respectively) with the previous dose, consideration should be given to reducing the dosage of carboplatin in single agent or combination regimens by 25%. A summary of these dose adjustments is given below:
a) If platelets are greater than 100,000 and neutrophils are greater than 2,000 – the adjusted dose is 125% from prior course.
b) If platelets are 50,000 – 100,000 and neutrophils are 500 – 2,000 there is no change of the dose from prior course.
c) If platelets are less than 50,000 and neutrophils are less than 500 the adjusted dose is 75% from prior course.
Combination therapy: The optimal use of carboplatin in combination with other myelosuppressive agents requires dosage adjustments according to the regimen and schedule to be adopted.
Paediatric population: As no sufficient experience of carboplatin use in children is available, no specific dosage recommendations can be given.
Elderly (over 65 years old): Dosage adjustment, initially or subsequently, may be necessary dependent on the physical conditions of the patient.
Dilution: The product may be diluted with 5% Glucose for Injection or 0.9% Sodium Chloride for Injection to concentrations as low as 0.5 mg/ml (500 micrograms/ml).
Advanced ovarian carcinoma: Initial Treatment: Carboplatin is indicated for the treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents.
Secondary Treatment: Carboplatin is indicated for the palliative treatment of patients with advanced ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.
Metastatic small cell carcinoma of the lung.
Carboplatin should not be used in patients with severe pre-existing renal impairment (creatinine clearance ≤20 ml/minute). Carboplatin should not be employed in severely myelosuppressed patients. Carboplatin is also contra-indicated in patients with hypersensitivity to carboplatin or other platinum containing compounds, or to mannitol. Carboplatin is contra-indicated in patients with bleeding tumours. Carboplatin is contra-indicated during breast feeding.
Carboplatin should be administered by individuals experienced in the use of anti-neoplastic therapy. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications. Carboplatin myelosuppression is closely related to its renal clearance: patients with abnormal kidney function or receiving concomitant therapy with other drugs with nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Renal function parameters should, therefore, be carefully assessed before and during therapy. Carboplatin courses should not be repeated more frequently than monthly under normal circumstances. Thombocytopenia, leucopenia and anaemia occur after administration of Carboplatin. Frequent monitoring of peripheral blood counts is recommended throughout and following therapy with carboplatin. Carboplatin combination therapy with other myelosuppressive compounds must be planned very carefully with respect to dosages and timing in order to minimise additive effects. Supportive transfusional therapy may be required in patients who suffer severe myelosuppression.
Carboplatin can cause nausea and vomiting. Pre-medication with anti-emetics and slower drug administration have been reported to be useful in reducing the incidence and intensity of these effects. Renal and hepatic function impairment may be encountered with carboplatin. Although no clinical evidence on compounding nephrotoxicity has been accumulated, it is recommended not to combine carboplatin with aminoglycosides or other nephrotoxic compounds. Very high doses of carboplatin (≥ 5 times single agent recommended dose) have resulted in severe abnormalities in hepatic and/or renal function. It is not clear whether an appropriate hydration programme might overcome effects on renal function. Dose reduction or discontinuation of therapy is required in the presence of moderate to severe alteration in renal or hepatic function test.
The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment. Impairment of renal function is also more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.
As for other platinum co-ordination compounds, allergic reactions to carboplatin have been reported. Infrequent allergic reactions to carboplatin have been reported, e.g. erythematous rash, fever with no apparent cause or pruritus. Rarely anaphylaxis, angio-oedema and anaphylactoid reactions including bronchospasm, urticaria and facial oedema have occurred. These reactions are similar to those observed after administration of other platinum containing compounds and they may occur within minutes of administration and should be managed with appropriate supportive therapy The incidence of allergic reactions may increase with previous exposure to platinum therapy; however, allergic reactions have been observed upon initial exposure to carboplatin. Patients should be observed carefully for possible allergic reactions and managed with appropriate supportive therapy, including antihistamines, adrenaline and/or glucocorticoids. Anaphylactic-like reactions may also occur as with other platinum co-ordination compounds. In patients pre-treated with platinum containing medicinal products, the risk of allergic reactions, including anaphylaxis, is increased.
Neurological evaluation and an assessment of hearing should be performed on a regular basis, especially in patients receiving high dose carboplatin. Neurotoxicity, such as parasthesia, decreased deep tendon reflexes, and ototoxicity are more likely seen in patients previously treated with other platinum treatments and other ototoxic agents.
In old age, renal function may be impaired, and should be taken into account for dosage, if necessary. Neurotoxic effects, especially in patients older than 65 years and/or those previously treated with cisplatin, have been reported. A relationship between visual transient disturbances and too high dosages in renally impaired patients has been reported. The carcinogenic potential of carboplatin has not been studied but compounds with similar mechanisms of action and mutagenicity have been reported to be carcinogenic. Men and women should use effective methods of contraception. Peripheral blood counts, renal and liver function tests and serum electrolytes should be monitored closely. Safety and efficacy of carboplatin in paediatric patients have not been established.
Peripheral blood counts and renal function tests should be monitored closely. Blood counts at the beginning of the therapy and weekly to assess haematological nadir for subsequent dose adjustment are recommended. Neurological evaluations should also be performed on a regular basis. In cases of prolonged leukocyte and platelet recovery, therapy with Carboplatin should not be restarted until a leucocyte count ≥2,000/μl and platelet count ≥100,000/μl has been achieved.
Myelosuppression (thrombocytopenia, Leucopenia, Neutropenia), Haemoglobin decrease, Anaemia, Haemorrhagic complications, Allergic reactions, Decreases in serum electrolytes (sodium, magnesium, potassium and calcium), peripheral neuropathies, persisting/ worsening of existing paraesthesia, Subclinical decrease in hearing acuity, Clinical ototoxicity, Nausea, vomiting, Painful gastro-intestinal disorders, Diarrhoea, constipation, Abnormalities of liver function tests, Alopecia, Renal toxicity, Hyperuricaemia, Asthenia, Malaise, urticaria, flu-like syndrome, erythematous rash, pruritis.
See prescribing information for full details.
Myelosuppression is worsened by therapy combining carboplatin with other compounds that are myelosuppressive. Carboplatin combination therapy with other myelosuppressive compounds must be planned very carefully with respect to dosage and timing in order to minimise additive effects.
Patients receiving concomitant therapy with other drug with nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Although no clinical evidence on compounding nephrotoxicity has been accumulated, it is recommended not to combine carboplatin with aminoglycosides or other nephrotoxic compounds. Administration of nephrotoxic and/or ototoxic drugs (e.g. aminoglycosides, vancomycin, capreomycin, loop diuretics) during treatment with carboplatin may increase organ toxicity of the drugs due to carboplatin induced changes in renal clearance of these substances.
Caution should be exercised when carboplatin in used concomitantly with warfarin, as cases increased INR have been reported.
Concomitant administration of carboplatin and complex forming compounds should be avoided as theoretically, the antineoplastic effects of carboplatin might be decreased. However, in animals and clinically, the antineoplastic effects of carboplatin were not influenced by diethylthiocarbamate. A decrease in phenytoin serum level has been reported following concomitant administration of carboplatin and phenytoin. This may lead to reappearance of seizures and may require an increase of phenytoin dosages.
Pregnancy and Lactation
Pregnancy: Carboplatin may cause embryonic/foetal harm when administered to a pregnant woman. Carboplatin should not be used during pregnancy unless clearly necessary. The mother should be informed about the risk to the foetus.
Lactation: It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to carboplatin treatment of the mother, breastfeeding must be discontinued if the mother is treated with carboplatin.
See prescribing information for full details.
Symptoms: Carboplatin was administered in Phase I studies at a dosage of up to 1600mg/m2 i.v. per course. At this dosage, life-threatening haematological side effects with granulocytopenia, thrombocytopenia and anaemia were observed. The granulocyte, thrombocyte and haemoglobin nadir were observed between days 9-25 (median: days 12-17). The granulocytes had reached values of ≥ 500/μl after 8-14 days (median: 11) and the thrombocytes values of ≥ 25.000/μl after 3-8 days (median: 7). The following non-haematological side effects also occurred: renal function disturbances with a 50% drop in the glomerular filtration rate, neuropathy, ototoxicity, sight loss, hyperbilirubinaemia, mucositis, diarrhoea, nausea and vomiting with headache, erythema, and severe infection. In the majority of cases, hearing disturbances were transient and reversible.
Therapy: There is no known antidote for carboplatin over dosage. The anticipated complications of over dosage would be related to myelosuppression as well as impairment of hepatic and renal function. Bone marrow transplantation and transfusions (thrombocytes, blood) can be effective measures of managing haematological side effects.
Effects on ability to drive and use machines: Carboplatin may cause nausea and vomiting, indirectly impairing the ability to drive and use machines.
Incompatibilities: This medicinal product should not be mixed with other medical products except those mentioned in the prescribing information. This product should not be used with aluminium-containing infusion assemblies, syringes and injection needles. The antineoplastic activity can be reduced.
Special precautions for storage: Store below 25°C. Do not refrigerate. Keep in the original package in order to protect from light.
Dilution: The product may be diluted with 5% Glucose for Injection, or 0.9% Sodium Chloride for Injection, to concentrations as low as 0.5 mg/ml (500 micrograms/ml). From a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. When diluted as directed, carboplatin solutions should be used within 12 hours when stored at room temperature (15 – 25°C) protected from light or within 24 hours when stored at 2 – 8°C if dilution is carried out under validated aseptic conditions. Since no antibacterial preservatives are contained in the formulation, it is recommended that any carboplatin solution be discarded 12 hours after dilution if stored at room temperature protected from light or after 24 hours, if stored under refrigeration. This product is for single dose use only.