Initial Treatment of Advanced Ovarian Carcinoma: PARAPLATIN (carbo-platin aqueous solution) 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 PARAPLATIN 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: 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.

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 PARAPLATIN.

Single-Agent Therapy: PARAPLATIN (carboplatin aqueous solution) INJECTION, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/mm²I. V. on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of PARAPLATIN 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:

PARAPLATIN—300 mg/mm² I. V. on day 1 every four weeks for six cycles (alternatively see Formula Dosing).

Cyclophosphamide—600 mg/mm² I. V. on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophos-phamide please refer to its package insert. (See Clinical Studies.)

Intermittent courses of PARAPLATIN 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 myelo-suppression 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

PARAPLATIN 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 carbo-platin 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 PARAPLATIN 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 PARAPLATIN 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 PARAPLATIN is calculatedin mg, not mg/mm².

The target AUC of 4-6 mg/mL•min using single-agent carboplatinappears 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 PARAPLATIN based on estimates of GFR should be used in elderly patients to provide predictable plasma PARAPLATIN AUCs and thereby minimize the risk of toxicity.

PREPARATION OF INTRAVENOUS SOLUTIONS

PARAPLATIN (carboplatin aqueous solution) INJECTION is a premixed aqueous solution of 10 mg/mL carboplatin.

PARAPLATIN aqueous solution can be further diluted to concentrations as low as 0. 5 mg/mL with 5% Dextrose in Water (D₅ W) or 0. 9% Sodium Chloride Injection, USP.

When prepared as directed, PARAPLATIN aqueous solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that PARAPLATIN aqueous solutions be discarded 8 hours after dilution.

PARAPLATIN®
(carboplatin aqueous solution) Injection

NDC 0015-3210-30 50 mg/5 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned.

NDC 0015-3211-30 150 mg/15 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned.

NDC 0015-3212-30 450 mg/45 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned.

NDC 0015-3216-30 600 mg/60 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned.

Storage

Unopened vials of PARAPLATIN (carboplatin aqueous solution) INJECTION are stable to the date indicated on the package when stored at 25°C (77°F); excursions permitted from 15°-30° C (59°-86° F) [see USP Controlled Room Temperature]. Protect from light.

PARAPLATIN (carboplatin aqueous solution) INJECTION multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25º 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

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.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.

2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA1985;253(11):1590-1592.

3. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983;1:426–428.

5. Jones RB, et al:Safe Handling of Chemotherapeutic Agents:A Report from the Mount Sinai Medical Center. CA–A Cancer Journal for Clinicians 1983; (Sept/Oct)258–263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033–1049.

7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996;53:1669-1685.

Bristol Myers Squibb Company, Princeton, NJ 08543. USA. Revised: January, 2004. FDA revision date: 1/9/2004

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