Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer

In two prospectively randomized, controlled studies conducted by the National Cancer Institute of Canada, Clinical Trials Group (NCIC) and the Southwest Oncology Group (SWOG), 789 chemotherapy naive patients with advanced ovarian cancer were treated with carboplatin or cisplatin, both in combination with cyclophos-phamide every 28 days for 6 courses before surgical reevaluation. The following results were obtained from both studies:

*114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study.

90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.

*Kaplan-Meier Estimates

Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis.

**Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.

*Kaplan-Meier Estimates

**Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.

Comparative Toxicity

The pattern of toxicity exerted by the carboplatin-containing regimen was significantly different from that of the cisplatin-containing combinations.  Differences between the two studies may be explained by different cisplatin dosages and by different supportive care.

The carboplatin-containing regimen induced significantly more thrombocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatin-containing regimen produced significantly more anemia in one study.  However, no significant differences occurred in incidences of infections and hemorrhagic episodes. 

Non-hematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxicity, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms.

*Values are in percent of evaluable patients.

**n.s.= not significant, p>0.05.

+May have been affected by cyclophosphamide dosage delivered. 

 *Values are in percent of evaluable patients.

**n.s.= not significant, p>0.05.

+May have been affected by cyclophosphamide dosage delivered.

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 achieved 6 clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71+ weeks.

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.

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.

Drug Interactions

The renal effects of nephrotoxic compounds may be potentiated by carboplatin.

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.

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.

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 1,942 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 dosage (see DOSAGE AND ADMINISTRATION).

Hematologic Toxicity

Bone marrow suppression is the dose-limiting toxicity of carboplatin. 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 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.

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/m2 IV 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 2,000 and the platelet count is at least 100,000.

Combination Therapy with Cyclophosphamide

In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of: Carboplatin Injection–300 mg/m2 IV on day 1 every 4 weeks for 6 cycles  (alternatively see Formula Dosing).

Cyclophosphamide–600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (see CLINICAL STUDIES).

Intermittent courses of Carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

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.

*Percentages apply to Carboplatin Injection as a single agent or to both carboplatin and cyclophosphamide in combination.  In the controlled studies, dosages were also adjusted at a lower level (50 to 60%) for severe myelosuppression.  Escalations above 125% were not recommended for these studies.

Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer.  No pre- or post-treatment hydration or forced diuresis is required.

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 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.

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 (see CLINICAL PHARMACOLOGY).  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 Injection target area under the concentration versus time curve (AUC in mg/mL•min), has been proposed by Calvert.  In these studies, GFR was measured by 51Cr-EDTA clearance.

The target AUC of 4 mg/mL•min to 6 mg/mL•min using single-agent carboplatin 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 administered to previously treated patients and the likelihood of developing toxicity.

Geriatric Dosing

Because renal function is often decreased in elderly patients, formula dosing of carboplatin based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin AUCs and thereby minimize the risk of toxicity.

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° to 30°C (59° to 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.

Handling and Disposal

Caution should be exercised in handling and preparing carboplatin injection. Several guidelines on this subject have been published. 1-4

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing carboplatin injection. If carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.