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adverse reactions
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY Bone Marrow Carboplatin USP Arm Percent Values are in percent of evaluable patients Cisplatin Arm Percent* P-Values ns=not significant, p>0.05 Thrombocytopenia <100,000/mm 3 70 29 <0.001 <50,000/mm 3 41 6 0.001 Neutropenia <2,000 cells/mm 3 97 96 ns <1,000 cells/mm 3 81 79 ns Leukopenia <4,000 cells/mm 3 98 97 ns <2,000 cells/mm 3 68 52 0.001 Anemia <11 g/dL 91 91 ns <18 g/dL 18 12 ns Infections 14 12 ns Bleeding 10 4 ns Transfusions 42 31 0.018 Gastrointestinal Nausea and vomiting 93 98 0.010 Vomiting 84 97 <0.001 Other GI side effects 50 62 0.013 Neurologic Peripheral neuropathies 16 42 <0.001 Ototoxicity 13 33 <0.001 Other sensory side effects 6 10 ns Central neurotoxicity 28 40 0.009 Renal Serum creatinine elevations 5 13 <0.001 Blood urea elevations 17 31 - Hepatic Bilirubin elevations 5 3 0.006 SGOT elevations 17 13 <0.001 Alkaline phosphatase elevations - - Electrolytes loss Sodium 10 20 0.005 Potassium 16 22 ns Calcium 16 19 ns Magnesium 63 88 <0.001 Other side effects Pain 36 37 ns Asthenia 40 33 ns Cardiovascular 15 19 ns Respiratory 8 9 ns Allergic 12 9 ns Genitourinary 10 10 ns Alopecia May have been affected by cyclophosphamide dosage delivered 50 62 0.017 Mucositis 10 9 ns ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY Bone Marrow Carboplatin USP Arm Percent Values are in percent of evaluable patients Cisplatin Arm Percent* P-Values ns=not significant, p>0.05 Thrombocytopenia <100,000/mm 3 59 35 <0.001 <50,000/mm 3 22 110.006 0.006 Neutropenia <2,000 cells/mm 3 95 97 ns <1,000 cells/mm 3 84 78 ns Leukopenia <4,000 cells/mm 3 97 97 ns <2,000 cells/mm 3 76 67 ns Anemia <11 g/dL 88 87 ns <18 g/dL 8 24 <0.001 Infections 18 21 ns Bleeding 6 4 ns Transfusions 25 33 ns Gastrointestinal Nausea and vomiting 94 96 ns Vomiting 52 91 0.0007 Other GI side effects 40 48 Neurologic Peripheral neuropathies 13 28 0.001 Ototoxicity 12 30 <0.001 Other sensory side effects 4 6 ns Central neurotoxicity 23 29 ns Renal Serum creatinine elevations 7 38 <0.001 Blood urea elevations - - - Hepatic Bilirubin elevations 5 3 ns SGOT elevations 23 16 ns Alkaline phosphatase elevations 29 20 ns Electrolytes loss Sodium - - - Potassium - - - Calcium - - - Magnesium 58 77 <0.001 Other side effects Pain 54 52 ns Asthenia 43 46 ns Cardiovascular 23 30 ns Respiratory 12 11 ns Allergic 10 11 ns Genitourinary 11 13 ns Alopecia May have been affected by cyclophosphamide dosage delivered 43 57 0.009 Mucositis 6 11 ns Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer In two prospective, randomized controlled studies in patients with advanced ovarian cancer previously treated with chemotherapy, carboplatin, USP achieved six clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71 + weeks.
adverse reactions
ADVERSE REACTIONS For a comparison of toxicities when carboplatin, USP 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 Bone Marrow First Line Combination Therapy 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, USP and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see CLINICAL STUDIES ). Percent Second Line Single Agent Therapy 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, USP. Percent 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 Hematologic Toxicity Bone marrow suppression is the dose-limiting toxicity of carboplatin injection. 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/mm3 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, USP, 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 injection. Transfusions have been administered to 26% of the patients treated with carboplatin, USP (44% of previously treated ovarian cancer patients). Bone marrow depression may be more severe when carboplatin injection 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, USP, 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, USP, 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, USP 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, USP (6% of pretreated ovarian cancer patients) with mild paresthesias occurring most frequently. Carboplatin, USP 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, USP. 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, USP 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, USP, 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, USP, 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, USP 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, USP 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, USP, and these electrolyte abnormalities were rarely associated with symptoms. Allergic Reactions Hypersensitivity to carboplatin, USP 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, i.e., 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.