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Carboplatin

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: CBDCA; Carboplatino; Carboplatinum; JM-8; Karboplatiini; Karboplatin; Karboplatina; NSC-241240
BAN: Carboplatin
USAN: Carboplatin
INN: Carboplatin [rINN (en)]
INN: Carboplatino [rINN (es)]
INN: Carboplatine [rINN (fr)]
INN: Carboplatinum [rINN (la)]
INN: Карбоплатин [rINN (ru)]
Chemical name: cis-Diammine(cyclobutane-1,1-dicarboxylato)platinum
Molecular formula: C6H12N2O4Pt =371.2
CAS: 41575-94-4
ATC code: L01XA02
Read code: y02m1

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Carboplatin). A colourless, crystalline powder. Sparingly soluble in water; very slightly soluble in alcohol and in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Carboplatin). A 1% solution in water has a pH of 5.0 to 7.0. Store in airtight containers. Protect from light.

Incompatibility. Carboplatin reacts with aluminium causing loss of potency and forming a precipitate. Needles, syringes, catheters or giving sets that contain aluminium should not be used for preparing or giving carboplatin.

Stability. About 5% of the initial carboplatin concentration was lost over 24 hours when solutions were diluted in sodium chloride 0.9% and stored at 25°; lesser amounts of degradation were seen at lower sodium chloride concentrations, but carboplatin was apparently stable over this period if diluted with glucose 5%. The authors suggested that chloride-containing infusion solutions are not suitable for carboplatin, not only because of the loss of active drug but because of the possibility that conversion to cisplatin may be occurring, with a risk of increased toxicity. This has been contested by the manufacturers (Bristol-Myers,

USA), who found that only 0.5% or 0.7%, depending on formulation, of a carboplatin solution in sodium chloride 0.9%, had been converted to cisplatin after 24 hours. However, the total degradation of carboplatin was not measured. In another study, the authors calculated the time to 5% degradation of carboplatin at 25° as 29.2 hours in sodium chloride 0.9% compared with 52.7 hours in water. They concluded that carboplatin should not be diluted in sodium chloride 0.9% when intended for continuous infusion over a prolonged period. Carboplatin in glucose 5% was reported to be stable for 7 days at 25° in PVC bags when protected from light.

Adverse Effects, Treatment, and Precautions

As for Cisplatin; nephrotoxicity and gastrointestinal toxicity are less severe than with cisplatin and reversible myelosuppression is the dose-limiting toxicity; platelet counts reach a nadir between 14 and 21 days after a dose, with recovery within 35 days, but recovery from leucopeniamay be slower. Myelosuppression may be more severe and prolonged in patients with impaired renal function. Carboplatin should therefore be given at reduced doses to these patients and should be avoided if creatinine clearance is 20 mL/minute or less. Weekly blood counts and regular renal and hepatic function tests are recommended in all patients during therapy. Neurological function including assessment of hearing should also be monitored.

Incidence of adverse effects. The manufacturers analysed the adverse effects of carboplatin in studies involving 710 patients. Myelosuppression was the dose-limiting toxicity: leucopenia occurred in 55% of the evaluable patients. Leucopenia and thrombocytopenia result in symptomatic events such as infection or bleeding in a minority of patients. Anaemia was frequent (59%) and required transfusional support in about one-fifth of the patients. Nephrotoxicity and serum electrolyte loss were much less of a problem; no high-volume fluid hydration or electrolyte supplementation was given during treatment. Vomiting occurred in about half the patients, and a further 25% had nausea without vomiting. Peripheral neurotoxicity was reported in 6% of evaluable patients and clinical ototoxicity occurred in only 8 cases or about 1 % (but see also Effects on the Ears, below). Increases in liver enzyme values have also been reported, as well as, more rarely, alopecia, skin rash, a flu-like syndrome, and local effects at the injection site.

Effects on the ears. Carboplatin is less ototoxic than cisplatin, but ototoxicity is still common with carboplatin when used in high doses, for example, as part of conditioning regimens for bone marrow transplantation. There was some evidence that sodium thiosulfate reduced carboplatin-induced hearing loss, when carboplatin was used for CNS malignancy.

Effects on the eyes. Cortical blindness developed in 2 patients with impaired renal function receiving high-dose carboplatin; although 10 cases of visual disturbances in patients receiving carboplatin had been reported to the manufacturers, none of these had sudden blindness and it was thought that the effect represented CNS toxicity in the presence of poor renal excretion. It was concluded that it was unwise to give high-dose carboplatin to patients whose glomerular filtration rate is less than 50 mL/minute.

Effects on the kidneys. Although carboplatin is reported to be much less nephrotoxic than cisplatin it is not devoid of adverse effects on the kidney. Salt wasting nephropathy (similar to that seen with cisplatin), and decreased creatinine clearance and glomerular filtration rate have occurred, as has acute renal failure, including in 2 patients given intraperitoneal carboplatin (although these patients had been heavily pretreated with cisplatin). It has been suggested that renal toxicity may be more likely at cumulative carboplatin doses of about 750 mg/m or more, and there is some evidence to suggest that intensive hydration may ameliorate nephrotoxic effects.

Hypersensitivity. In one series, 12% of 205 patients treated with carboplatin developed a hypersensitivity reaction after a median of 8 courses of platinum therapy. Symptoms were at least moderately severe in half of the patients. Reactions to cisplatin would be anticipated in patients who have been previously sensitised to carboplatin — for 1 such case see site. In another study, patients receiving more than 7 courses of carboplatin therapy were given a skin test before each course in an attempt to identify patients at risk for hypersensitivity reactions. The test consisted of 0.02 mL of an undiluted aliquot of their planned infusion, injected intradermally 1 hour before the dose. A negative skin test accurately predicted the absence of a hypersensitivity reaction. In a further extended report by the same group, the skin test had been given about 30 minutes before carboplatin doses in 126 women who had already received at least 6 courses of a platinum-based regimen for a gynaecological cancer. Of 668 negative skin tests, a hypersensitivity reaction developed on 10 occasions (in 7 patients), giving a false-negative rate of 1.5%. None of the reactions were severe. Of the 39 patients who had a positive skin test, 7 elected to receive the dose of carboplatin; 6 of these developed a hypersensitivity reaction but none were severe.

The use of a desensitisation regimen has been successful in a small number of patients, although others have not found it useful.

Pregnancy. For a report of the successful use of carboplatin-based chemotherapy during pregnancy, with no adverse effects on the infant, see Pregnancy, under Cisplatin.

Interactions

As for Cisplatin.

Pharmacokinetics

Intravenous carboplatin exhibits a biphasic elimination and is excreted primarily in the urine, about 70% of a dose being excreted within 24 hours, almost all unchanged. The terminal half-life of intact carboplatin is reported to be about 1.5 to 6 hours. Platinum from carboplatin slowly becomes protein bound, and is subsequently excreted with a half-life of 5 days or more.

Uses and Administration

Carboplatin is an analogue of cisplatin with similar actions and uses. It is used in the treatment of advanced ovarian cancers and of small-cell lung cancer, both alone and combined with other antineoplastics. It has also been tried as an alternative to cisplatin in other solid tumours (see below). Carboplatin is given by intravenous infusion over 15 minutes to 1 hour. In the UK an initial dose of 400 mg/m is licensed for use as a single agent in previously untreated patients with normal renal function, reduced by 20 to 25% (300 to 320 mg/m) in patients who have previously been treated with myelosuppres-sive therapy or who have poor performance status. In the United States of America (US and USA) an initial dose of 360 mg/m is licensed as a single agent in previously treated patients with recurrent disease, and an initial dose of 300 mg/m when used with cyclophosphamide in previously untreated patients.

Dosage adjustments are necessary in patients with renal impairment (see below) and when carboplatin is given as part of a combination regimen. The dose in mg may be calculated using the Calvert formula as described under Administration, below. Subsequent doses should be adjusted according to the nadir of the white cell and platelet counts (see also Bone-marrow Depression), and should not be given more frequently than every 4 weeks.

Administration. Pharmacokinetic studies by Calvert and colleagues have indicated that the dose of carboplatin to produce a desired area under the concentration-time curve (AUC) could be calculated, based on the patient’s glomerular filtration rate (GFR), as:

Dose in mg = target AUC x (GFR + 25)

It should be noted that the resultant dose is given in mg and not in mg/m. This formula was found to be useful in patients with higher than normal as well as reduced GFR. Suggested target AUCs were 5 mg/mL per minute in previously treated patients and 7 mg/mL per minute in those who had not previously received chemotherapy. In combination therapy the appropriate AUC value depended on the other drugs used: an AUC of 4.5 mg/mL per minute gave acceptable results when carboplatin was used with bleomycin and etoposide for testicular teratoma.

However, determination of GFR may be a problem: clearance of technetium-99m-labelled diethylenetriamine penta-acetic acid (DTPA) or chromium-51-labelled edetic acid is more accurate than 24-hour creatinine clearance, with the first of these more convenient than the second. (It has been suggested that creatinine clearance should not be used to estimate GFR for the Calvert equation.) Nonetheless, radioisotopic determination of GFR is still an elaborate procedure, and may be less accurate in children than adults Chatelut and colleagues have proposed formulae for determining clearance of carboplatin in both adults and children.

It has been suggested that the Calvert and Chatelut formulae are not sufficiently accurate for use in children, or in adults with very severe renal impairment. Bayesian methods are the technique of choice where serum carboplatin concentrations can be monitored. However, a study in children showed that dosage based on determination of the GFR results in more consistent carboplatin exposure than dosage based on body-surface area.

Administration in renal impairment. The initial dose of carboplatin is usually determined using a formula (see Administration, above). If this approach is not adopted, the UK licensed product information recommends the following doses based on the patient’s creatinine clearance (CC):

• CC 40mL/minute or more: 400mg/m

• CC 20 to 39 mL/mmute: 250 mg/m

However, in the United States of America, the licensed information recommends:

• CC 41 to 59 mL/mmute: 250 mg/m

• CC 16 to 40 mL/mmute: 200 mg/m

Malignant neoplasms. A preliminary review of carboplatin, concluded that it was active in ovarian cancer, with similar responses to those seen with cisplatin; its activity in small-cell lung cancer, seminoma, and squamous cell carcinomas of the head and neck seemed likely to be comparable, whereas results in gastrointestinal and breast cancers, lymphomas and leukaemias, melanoma, mesothelioma, renal carcinoma, and sarcoma were, generally unimpressive. A subsequent review suggested that in testicular cancer, where there was a prospect of cure, cisplatin, which appeared to give better results in some studies should be preferred. However, in ovarian cancer, where treatment was largely palliative, carboplatin had the advantage of being better tolerated. A further review of randomised studies concurred that carboplatin was equivalent to cisplatin in suboptimally debulked ovarian cancer and extensive-stage small-cell lung cancer, and was inferior to cisplatin in testicular cancer. It was also concluded that carboplatin was inferior to cisplatin in head and neck and oesophageal cancers. There was insufficient comparative evidence for other cancers for which cisplatin has a role.

Preparations

British Pharmacopoeia 2008: Carboplatin Injection;

The United States Pharmacopeia 31, 2008: Carboplatin for Injection.

Proprietary Preparations

Argentina: Carbokebir; Carboplat; Carboxtie; Omilipis; Paraplatin ;

Austria; Carbosol; Paraplatin;

Belgium: Carbosin; Paraplatin;

Brazil: B-Platin; Biocarbo; Displata ; Evocarb ; Oncocarb ; Oncoplatin; Paraplatin; Platamine; Platicarb ; Tecnocarb; Vancel;

Canada: Paraplatin;

Chile: Blastocarb ; Onco-carb; Paraplatin;

Czech Republic: Cycloplatin; Paraplatin ;

Denmark: Paraplatin;

Finland: Carbosin ; Paraplatin;

France: Paraplatine;

Germany; Carbocell; Carbomedac; Carboplat; Neocarbo; Ribocarbo;

Greece: Carboplamin; Carbosin; Emorzim; Megaplatin; Paraplatin;

Hong Kong; Paraplatin;

Hungary: Cycloplatin; Paraplatin;

India: Biocarb; Cytocarb; Kemocarb;

Indonesia: Carbosin; Paraplatin;

Ireland: Paraplatin;

Israel: Paraplatin ;

Italy: Paraplatin;

Malaysia: Carbosin; Paraplatin ;

Mexico: Blastocarb; Boplatex; Carboplat; Carbotec; Ifacap; Kemocarb; Paraplatin;

The Netherlands: Carbosin; Paraplatin-P;

Norway: Carbosin; Paraplatin;

New Zealand: Carbosin ; Paraplatin;

Philippines: Biovinate; Bonaplatin; Carbotinol; Crobextin; Kemocarb; Paraplatin;

Poland: Cycloplatin; Paraplatin;

Portugal: Nealorin; Novoplatinum; Paraplatin;

Russia: Blastocarb; Cycloplatin; Paraplatin;

South Africa: Carbosin; Paraplatin;

Singapore: Paraplatin;

Spain: Nealorin; Paraplatin; Platinwas;

Sweden: Paraplatin;

Switzerland: Paraplatin;

Thailand: Blastocarb; Carbosin; Kemocarb; Paraplatin;

Turkey: Carbosin; Paraplatin; Platinwas;

United Kingdom (UK): Paraplatin;

United States of America (US and USA): Paraplatin;

Venezuela: Bioplatinex; Oplat.

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