WARNINGS
Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during PARAPLATIN treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single-agent PARAPLATIN. In general, single intermittent courses of PARAPLATIN should not be repeated until leukocyte, neutrophil, and platelet counts have recovered.
Since anemia is cumulative, transfusions may be needed during treatment with PARAPLATIN, particularly in patients receiving prolonged therapy.
Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial PARAPLATIN dosages in these patients should be appropriately reduced (see DOSAGE AND ADMINISTRATION) and blood counts should be carefully monitored between courses. The use of PARAPLATIN in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects.
PARAPLATIN has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when PARAPLATIN was administered at higher than recommended doses in combination with other ototoxic agents.
PARAPLATIN can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of PARAPLATIN, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over five consecutive daily pulse doses has resulted in reduced emesis.
Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving PARAPLATIN as secondary treatment.
Loss of vision, which can be complete for light and colors, has been reported after the use of PARAPLATIN with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.
As in the case of other platinum-coordination compounds, allergic reactions to PARAPLATIN have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions.)
High dosages of PARAPLATIN (more than four times the recommended dose) have resulted in severe abnormalities of liver function tests.
PARAPLATIN may cause fetal harm when administered to a pregnant woman. PARAPLATIN has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS
General
Needles or intravenous administration sets containing aluminum parts that may come in contact with PARAPLATIN should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and loss of potency.
Drug Interactions
The renal effects of nephrotoxic compounds may be potentiated by PARAPLATIN.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy.
Pregnancy
Pregnancy Category D (see WARNINGS).
Nursing Mothers
It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to PARAPLATIN treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with PARAPLATIN (carboplatin lyophilized powder) for INJECTION.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established (see WARNINGS; “audiologic toxicity”).
Geriatric Use
Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1942 patients (414 were ≥65 years of age) that received single-agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of PARAPLATIN dosage (see DOSAGE AND ADMINISTRATION).
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