Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1982
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carboplatin (Injection, Solution)
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NOTE: Aluminum reacts with carboplatin Injection 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 Injection.<br/>Single-Agent Therapy: Carboplatin Injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/mIV on day 1 every 4 weeks
(alternatively see Formula Dosing).
In general, however, single intermittent courses of carboplatin injection should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.<br/>Combination Therapy with Cyclophosphamide: In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of: Carboplatin Injection���300 mg/mIV on day 1 every four weeks for six cycles (alternatively see Formula Dosing). Cyclophosphamide���600 mg/mIV on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert. Intermittent courses of carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.<br/>Dose Adjustment Recommendations: Pretreatment platelet count and performance
status are important prognostic factors for severity of myelosuppression in
previously treated patients. The suggested dose adjustments
for single agent or combination therapy shown in the table below are modified
from controlled trials in previously treated and untreated patients with ovarian
carcinoma. Blood counts were done weekly, and the recommendations are based
on the lowest post-treatment platelet or neutrophil value. Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.<br/>Patients with Impaired Kidney Function: Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single-agent carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used. The data available for patients with severely impaired
kidney function (creatinine clearance below 15 mL/min) are too limited to
permit a recommendation for treatment. 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.<br/>Formula Dosing: Another approach for determining the
initial dose of carboplatin Injection is the use of mathematical formulae, which are
based on a patient's pre-existing renal function or renal function and desired
platelet nadir. Renal excretion is the major route of elimination for carboplatin.
The use
of dosing formulae, as compared to empirical dose calculation based on body
surface area, allows compensation for patient variations in pretreatment renal
function that might otherwise result in either underdosing (in patients with
above average renal function) or overdosing (in patients with impaired renal
function). A simple formula for calculating dosage,
based upon a patient's glomerular filtration rate (GFR in mL/min) and carboplatin
target area under the concentration versus time curve (AUC in mg/mL���min),
has been proposed by Calvert. In these studies, GFR was measured byCr-EDTA
clearance. The target AUC of 4-6 mg/mL���min using single-agent carboplatin Injection appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single-agent carboplatin Injection administered to previously treated patients and the likelihood of developing toxicity.<br/>Geriatric Dosing: Because renal function is often decreased in elderly patients, formula dosing of carboplatin Injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin AUCs and thereby minimize the risk of toxicity.<br/>PREPARATION OF INTRAVENOUS SOLUTIONS: Carboplatin Injection is a premixed aqueous solution of 10 mg/mL carboplatin. Carboplatin Injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (DW) or 0.9% Sodium Chloride Injection, USP. When prepared as directed, carboplatin Injection are stable for 8 hours at room temperature (25��C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin Injection be discarded 8 hours after dilution.
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Carboplatin Injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of Carboplatin. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine[1,1-cyclobutane-dicarboxylato(2-)-O,O���]-,(SP-4-2), and carboplatin has the following structural formula: Carboplatin is a crystalline powder with the molecular formula of CHNOPt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide. Each ml of carboplatin injection contains 10 mg of carboplatin in water for injection, with no other inactive ingredients, pH range is 5.0-7.0. It is supplied as 5 ml, 15 ml&45 ml multi dose vials.
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Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein crosslinks.
This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce
the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and
biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the
difference in aquation rates. In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 to 500 mg/mof
carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). 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. The Cvalues and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 to 500 mg/m). Carboplatin is not bound to plasma proteins. No significant quantities
of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3 to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs. In patients with creatinine clearances below 60 mL/min, the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should therefore be reduced in these patients . The primary determinant of carboplatin clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR to provide predictable carboplatin plasma AUCs should be used in elderly patients to minimize the risk of toxicity.
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Carboplatin Injection is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds. Carboplatin Injection should not be employed in patients with severe bone marrow depression or significant bleeding.
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Carboplatin Injection NDC 41616-150-40 50
mg/5 mL aqueous solution in multidose vials (with orange flip-off seals),
individually cartoned. NDC 41616-151-40 150
mg/15 mL aqueous solution in multidose vials (with orange flip-off seals),
individually cartoned. NDC 41616-300-40 450
mg/45 mL aqueous solution in multidose vials (with orange flip-off seals),
individually cartoned.<br/>Storage: Unopened vials of carboplatin Injection are stable to the date indicated on the package when stored at 25��C (77��F);excursions permitted from 15��-30��C (59��-86��F) [see USP Controlled Room Temperature]. Protect from light. Carboplatin Injection multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25��C following multiple needle entries. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Solutions for infusion should be discarded 8 hours after preparation.<br/>Handling and Disposal: Procedures for proper handling and disposal of anti-cancer
drugs should be considered. Several guidelines on this subject have been published.There
is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate.
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WARNING: Carboplatin Injection should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and
complications is possible only when adequate treatment facilities are readily available. Bone marrow suppression is dose related and may be severe, resulting
in infection and/or bleeding. Anemia may be cumulative and may require transfusion
support. Vomiting is another frequent drug-related side effect. Anaphylactic-like reactions to carboplatin have been reported and
may occur within minutes of carboplatin administration. Epinephrine, corticosteroids,
and antihistamines have been employed to alleviate symptoms.
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General: Needles or intravenous administration sets containing aluminum
parts that may come in contact with Carboplatin Injection should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and
loss of potency.<br/>Drug Interactions: The renal effects of nephrotoxic compounds may be potentiated by carboplatin.<br/>Carcinogensis, 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.<br/>Pregnancy:<br/>Pregnancy Category D: .<br/>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 carboplatin treatment of the mother, it is recommended
that breast feeding be discontinued if the mother is treated with carboplatin Injection.<br/>Pediatric Use: Safety and effectiveness in pediatric
patients have not been established (see WARNINGS;���audiologic toxicity���).<br/>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 carboplatin Injection dosage .
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There is no known antidote for carboplatin Injection overdosage. The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity.
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CARBOPLATIN
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carboplatin (Injection, Solution)
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For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES: Comparative Toxicity. In the narrative section that follows, the incidences of adverse events are based on data from 1893 patients with various types of tumors who received carboplatin as single-agent therapy.<br/>Hematologic Toxicity: Bone marrow suppression is the dose-limiting toxicity of Carboplatin Injection. Thrombocytopenia with platelet counts below 50,000/mmoccurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1000/mmoccurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2000/mmoccurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single-agent therapy. By day 28, 90% of patients have platelet counts above 100,000/mm; 74% have neutrophil counts above 2000/mm; 67% have leukocyte counts above 4000/mm. Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leukopenia and thrombocytopenia. The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic complications in 5% of the patients treated with carboplatin, with drug related death occurring in less than 1% of the patients. Fever has also been reported in patients with neutropenia. Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who started therapy with a baseline above that value. The incidence of anemia increases with increasing exposure to carboplatin. Transfusions have been administered to 26% of the patients treated with carboplatin (44% of previously treated ovarian cancer patients). Bone marrow depression may be more severe when carboplatin is combined with other bone marrow suppressing drugs or with radiotherapy.<br/>Gastrointestinal Toxicity: Vomiting occurs in 65% of the patients (81% of previously treated
ovarian cancer patients) and in about one-third of these patients it is severe.
Carboplatin, as a single agent or in combination, is significantly less emetogenic
than cisplatin; however, patients previously treated with emetogenic agents,
especially cisplatin, appear to be more prone to vomiting. Nausea alone occurs
in an additional 10% to 15% of patients. Both nausea and vomiting usually
cease within 24 hours of treatment and are often responsive to antiemetic
measures. Although no conclusive efficacy data exist with the following schedules,
prolonged administration of carboplatin, either by continuous 24-hour infusion
or by daily pulse doses given for 5 consecutive days, was associated with
less severe vomiting than the single-dose intermittent schedule. Emesis was
increased when carboplatin was used in combination with other emetogenic compounds.
Other gastrointestinal effects observed frequently were pain, in 17% of the
patients; diarrhea, in 6%; and constipation, also in 6%.<br/>Neurologic Toxicity: Peripheral neuropathies have been observed in 4% of the patients
receiving carboplatin (6% of pretreated ovarian cancer patients) with mild
paresthesias occurring most frequently. Carboplatin therapy produces significantly
fewer and less severe neurologic side effects than does therapy with cisplatin.
However, patients older than 65 years and/or previously treated with cisplatin
appear to have an increased risk (10%) for peripheral neuropathies. In 70%
of the patients with pre-existing cisplatin-induced peripheral neurotoxicity,
there was no worsening of symptoms during therapy with carboplatin. Clinical
ototoxicity and other sensory abnormalities such as visual disturbances and
change in taste have been reported in only 1% of the patients. Central nervous
system symptoms have been reported in 5% of the patients and appearto be
most often related to the use of antiemetics. Although the overall incidence of peripheral neurologic side effects
induced by carboplatin is low, prolonged treatment, particularly in cisplatin
pretreated patients, may result in cumulative neurotoxicity.<br/>Nephrotoxicity: Development of abnormal renal function test results is uncommon,
despite the fact that carboplatin, unlike cisplatin, has usually been administered
without high-volume fluid hydration and/or forced diuresis. The incidences
of abnormal renal function tests reported are 6% for serum creatinine and
14% for blood urea nitrogen (10% and 22%, respectively, in pretreated ovarian
cancer patients). Most of these reported abnormalities havebeen mild and
about one-half of them were reversible. Creatinine clearance has proven to be the most sensitive measure
of kidney function in patients receiving carboplatin, and it appears to be
the most useful test for correlating drug clearance and bone marrow suppression.
Twenty-seven percent of the patients who had a baseline value of 60 mL/min
or more demonstrated a reduction below this value during carboplatin therapy.<br/>Hepatic Toxicity: The incidences of abnormal liver function tests in patients with
normal baseline values were reported as follows: total bilirubin, 5%; SGOT,
15%; and alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated
ovarian cancer patients). These abnormalities have generally been mild and
reversible in about one-half of the cases, although the role of metastatic
tumor in the liver may complicate the assessment in many patients. In a limited
series of patients receiving very high dosages of carboplatin and autologous
bone marrow transplantation, severe abnormalities of liver function tests
were reported.<br/>Electrolyte Changes: The incidences of abnormally decreased serum electrolyte values
reported were as follows: sodium, 29%; potassium, 20%; calcium, 22%; and magnesium,
29%; (47%, 28%, 31%, and 43%, respectively, in pretreated ovarian cancer patients).
Electrolyte supplementation was not routinely administered concomitantly with
carboplatin, and these electrolyte abnormalitieswere rarely associated with
symptoms.<br/>Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of the
patients. These allergic reactions have been similar in nature and severity
to those reported with other platinum-containing compounds, ie, rash, urticaria,
erythema, pruritus, and rarely bronchospasm and hypotension. Anaphylactic
reactions have been reported as part of postmarketing surveillance . These reactions have been successfully
managed with standard epinephrine, corticosteroid, and antihistamine therapy.<br/>Injection Site Reactions: Injection site reactions, including redness, swelling, and pain,
have been reported during postmarketing surveillance. Necrosis associated
with extravasation has also been reported.<br/>Other Events: Pain and asthenia were the most frequently reported miscellaneous adverse effects; their relationship to the tumor and to anemia was likely. Alopecia was reported (3%). Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in 6% or less of the patients. Cardiovascular events (cardiac failure, embolism, cerebrovascular accidents) were fatal in less than 1% of the patients and did not appear to be related to chemotherapy. Cancer-associated hemolytic uremic syndrome has been reported rarely. Malaise, anorexia and hypertension have been reported as part of postmarketing surveillance.
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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 carboplatin
treatment and, when appropriate, until recovery is achieved. Median nadir
occurs at day 21 in patients receiving single-agent carboplatin. In general,
single intermittent courses of carboplatin should not be repeated until leukocyte,
neutrophil, and platelet counts have recovered. Since
anemia is cumulative, transfusions may be needed during treatment with carboplatin,
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 carboplatin dosages in these
patients should be appropriately reduced (see DOSAGE
AND ADMINISTRATION) and blood counts should be carefully monitored
between courses. The use of carboplatin in combination with other bone marrow
suppressing therapies must be carefully managed with respect to dosage and
timing in order to minimize additive effects. Carboplatin 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 carboplatin was administered at higher than recommended doses in combination with other ototoxic agents. Carboplatin 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 carboplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over 5 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 carboplatin as secondary treatment. Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin 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 carboplatin 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. High dosages of carboplatin (more than four times the recommended dose) have resulted in severe abnormalities of liver function tests. Carboplatin Injection may cause fetal harm when administered to a pregnant woman. Carboplatin 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.
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carboplatin
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