Carboplatin (Carboplatin) - Indications and Dosage

INDICATIONS & USAGE SECTION

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 Injection and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin vs. 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.

DOSAGE & ADMINISTRATION SECTION

NOTE: Aluminum reacts with carboplatin 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.

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 2000 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 four weeks for six cycles (alternatively see Formula Dosing).

Cyclophosphamide - 600 mg/m² IV on day 1 every four weeks for six 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 2000 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 Injection 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.

*

Platelets	Neutrophils	Adjusted Dose* (From Prior Course)
>100,000	>2000	125%
50-100,000	500-2000	No Adjustment
<50,000	<500	75%

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 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.

Baseline Creatinine Clearance	Recommended Dose on Day 1
41 - 59 mL/min	250 mg/m2
16 - 40 mL/min	200 mg/m2

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 preexisting 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.

CALVERT FORMULA FOR CARBOPLATIN DOSING

Total Dose (mg) = (target AUC) x (GFR + 25)
Note: With the Calvert formula, the total dose of Carboplatin Injection is calculated in mg, not mg/m 2 .

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.

% Actual Toxicity in Previously Treated Patients

	Gr 3 or Gr 4	Gr 3 or Gr 4
AUC (mg/mL(min)	Thrombocytopenia	Leukopenia
4 to 5	16%	13%
6 to 7	33%	34%

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 Injection AUCs and thereby minimize the risk of toxicity.

Preparation Of Intravenous Solutions

Carboplatin Injection 10 mg/mL is supplied as a Ready To Use (RTU) sterile solution in 5 mL, 15 mL, 45 mL or 60 mL vials. Total content of carboplatin per vial is described in following table:

Vial Strength	Diluent Volume
50 mg	5 mL
150 mg	15 mL
450 mg	45 mL
600 mg	60 mL

Carboplatin Injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D₅W) or 0.9% Sodium Chloride Injection, USP.

When further diluted, Carboplatin Injection solutions 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 solutions be discarded 8 hours after dilution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

HOW SUPPLIED SECTION

Carboplatin Injection 10 mg/mL sterile solution is available in the following presentations:

NDC 61703-339-18 50 mg/5 mL vials, individually cartoned. (Blue flip-off seals)

NDC 61703-339-22 150 mg/15 mL vials, individually cartoned. (Blue flip-off seals)

NDC 61703-339-50 450 mg/45 mL vials, individually cartoned. (Blue flip-off seals)

NDC 61703-339-56 600 mg/60 mL vials, individually cartoned. (Blue flip-off seals)

STORAGE

Unopened vials of Carboplatin Injection are stable for the life indicated on the package when stored at 25°C (77°F) [excursions permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature] and protected from light.

Carboplatin injection multidose vials maintain microbial, chemical, and physical stability for up to 15 days at 25°C following multiple needle entries.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published^1-7. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.