Carboplatin
Generic: CARBOPLATIN
Basic Information
Manufacturer
Fresenius Kabi USA, LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
b4fa7aac-c9d2-4af4-a281-3e6cfc502ff6
Indications & Usage
INDICATIONS: Initial Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents.
One established combination regimen consists of carboplatin and cyclophosphamide.
Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES ).
There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.
Secondary Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.
Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.
Initial Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents.
One established combination regimen consists of carboplatin and cyclophosphamide.
Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES ).
There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.
Secondary Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.
Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.
One established combination regimen consists of carboplatin and cyclophosphamide.
Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES ).
There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.
Secondary Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.
Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.
Initial Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents.
One established combination regimen consists of carboplatin and cyclophosphamide.
Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES ).
There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.
Secondary Treatment of Advanced Ovarian Carcinoma Carboplatin Injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.
Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.
Warnings
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 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 (see CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions ).
High dosages of carboplatin (more than 4 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.
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 (see CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions ).
High dosages of carboplatin (more than 4 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.
Adverse Reactions
ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES , Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer, Comparative Toxicity.
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER First Line Combination Therapy * Percent Second Line Single Agent Therapy ** Percent Bone Marrow Thrombocytopenia < 100,000/mm 3 66 62 < 50,000/mm 3 33 35 Neutropenia < 2,000 cells/mm 3 96 67 < 1,000 cells/mm 3 82 21 Leukopenia < 4,000 cells/mm 3 97 85 < 2,000 cells/mm 3 71 26 Anemia < 11/g/dL 90 90 < 8 g/dL 14 21 Infections 16 5 Bleeding 8 5 Transfusions 35 44 Gastrointestinal Nausea and vomiting 93 92 Vomiting 83 81 Other GI side effects 46 21 Neurologic Peripheral neuropathies 15 6 Ototoxicity 12 1 Other sensory side effects 5 1 Central neurotoxicity 26 5 Renal Serum creatinine elevations 6 10 Blood urea elevations 17 22 Hepatic Bilirubin elevations 5 5 SGOT elevations 20 19 Alkaline phosphatase elevations 29 37 Electrolytes loss Sodium 10 47 Potassium 16 28 Calcium 16 31 Magnesium 61 43 Other side effects Pain 44 23 Asthenia 41 11 Cardiovascular 19 6 Respiratory 10 6 Allergic 11 2 Genitourinary 10 2 Alopecia 49 2 Mucositis 8 1 *Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see CLINICAL STUDIES ).
Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table.
**Single Agent Use for the Secondary Treatment of Ovarian Cancer Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single-agent carboplatin.
In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single-agent therapy.
Hematologic Toxicity Bone marrow suppression is the dose-limiting toxicity of carboplatin.
Thrombocytopenia with platelet counts below 50,000/mm 3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm 3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm 3 occurs 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 3 ; 74% have neutrophil counts above 2,000/mm 3 ; 67% have leukocyte counts above 4,000/mm 3 .
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.
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%.
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 appear to 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.
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 have been 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.
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.
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 abnormalities were rarely associated with symptoms.
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 (see WARNINGS ).
These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy.
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.
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, hypertension, dehydration, and stomatitis have been reported as part of postmarketing surveillance.
Hematologic Toxicity Bone marrow suppression is the dose-limiting toxicity of carboplatin.
Thrombocytopenia with platelet counts below 50,000/mm 3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm 3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm 3 occurs 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 3 ; 74% have neutrophil counts above 2,000/mm 3 ; 67% have leukocyte counts above 4,000/mm 3 .
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.
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%.
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 appear to 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.
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 have been 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.
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.
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 abnormalities were rarely associated with symptoms.
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 (see WARNINGS ).
These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy.
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.
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, hypertension, dehydration, and stomatitis have been reported as part of postmarketing surveillance.
For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES , Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer, Comparative Toxicity.
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER First Line Combination Therapy * Percent Second Line Single Agent Therapy ** Percent Bone Marrow Thrombocytopenia < 100,000/mm 3 66 62 < 50,000/mm 3 33 35 Neutropenia < 2,000 cells/mm 3 96 67 < 1,000 cells/mm 3 82 21 Leukopenia < 4,000 cells/mm 3 97 85 < 2,000 cells/mm 3 71 26 Anemia < 11/g/dL 90 90 < 8 g/dL 14 21 Infections 16 5 Bleeding 8 5 Transfusions 35 44 Gastrointestinal Nausea and vomiting 93 92 Vomiting 83 81 Other GI side effects 46 21 Neurologic Peripheral neuropathies 15 6 Ototoxicity 12 1 Other sensory side effects 5 1 Central neurotoxicity 26 5 Renal Serum creatinine elevations 6 10 Blood urea elevations 17 22 Hepatic Bilirubin elevations 5 5 SGOT elevations 20 19 Alkaline phosphatase elevations 29 37 Electrolytes loss Sodium 10 47 Potassium 16 28 Calcium 16 31 Magnesium 61 43 Other side effects Pain 44 23 Asthenia 41 11 Cardiovascular 19 6 Respiratory 10 6 Allergic 11 2 Genitourinary 10 2 Alopecia 49 2 Mucositis 8 1 *Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see CLINICAL STUDIES ).
Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table.
**Single Agent Use for the Secondary Treatment of Ovarian Cancer Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single-agent carboplatin.
In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single-agent therapy.
Hematologic Toxicity Bone marrow suppression is the dose-limiting toxicity of carboplatin.
Thrombocytopenia with platelet counts below 50,000/mm 3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm 3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm 3 occurs 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 3 ; 74% have neutrophil counts above 2,000/mm 3 ; 67% have leukocyte counts above 4,000/mm 3 .
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.
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%.
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 appear to 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.
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 have been 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.
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.
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 abnormalities were rarely associated with symptoms.
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 (see WARNINGS ).
These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy.
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.
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, hypertension, dehydration, and stomatitis have been reported as part of postmarketing surveillance.
Hematologic Toxicity Bone marrow suppression is the dose-limiting toxicity of carboplatin.
Thrombocytopenia with platelet counts below 50,000/mm 3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm 3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm 3 occurs 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 3 ; 74% have neutrophil counts above 2,000/mm 3 ; 67% have leukocyte counts above 4,000/mm 3 .
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.
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%.
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 appear to 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.
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 have been 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.
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.
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 abnormalities were rarely associated with symptoms.
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 (see WARNINGS ).
These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy.
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.
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, hypertension, dehydration, and stomatitis have been reported as part of postmarketing surveillance.