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Paraplatin

Brand Name:	Paraplatin	Trade Name:	carboplatin
FDA Approved For:	Initial treatment of advanced ovarian carcinoma: PARAPLATIN is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of PARAPLATIN and cyclophosphamide (CYTOXAN )… Secondary treatment of advanced ovarian carcinoma: PARAPLATIN 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.	Pediatric Use:	Safety and effectiveness in pediatric patients have not been established.
Carcinogen:	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.	Mutagen:	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.
Manufacturer and/or Distributor:	Bristol-Myers Squibb

Adverse Reactions:

For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see the CLINICAL PHARMACOLOGY: CLINICAL STUDIES: Comparative Toxicity subsection. ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER (See Table) Hematologic toxicity: Bone marrow suppression is the dose-limiting toxicity of PARAPLATIN. Thrombocytopenia with platelet counts below 50,000/ mm3 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/ mm3 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/ mm3; 74% have neutrophil counts above 2,000/ mm3; 67% have leukocyte counts above 4,000/ mm3. Marrow suppression is usually more severe in patients with impaired kidney function. Patients with p.o. 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 PARAPLATIN (carboplatin for injection), 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 PARAPLATIN. Transfusions have been administered to 26% of the patients treated with PARAPLATIN (44% of previously treated ovarian cancer patients). Bone marrow depression may be more severe when PARAPLATIN 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 PARAPLATIN, either by continuous 24-hour infusion or by daily pulse doses given for five consecutive days, was associated with less severe vomiting than the single dose intermittent schedule. Emesis was increased when PARAPLATIN 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 PARAPLATIN (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 PARAPLATIN. 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 PARAPLATIN 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 PARAPLATIN, 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 PARAPLATIN 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 PARAPLATIN 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 PARAPLATIN, and these electrolyte abnormalities were rarely associated with symptoms. Allergic reactions: Hypersensitivity to PARAPLATIN 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. These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy. 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.)

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