Carboplatin

CARBOPLATIN- carboplatin injection, solution
Sandoz Inc

Rx Only

WARNING

Carboplatin injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available.

Bone marrow suppression is dose related and may be severe, resulting in infection and/or bleeding. Anemia may be cumulative and may require transfusion support. Vomiting is another frequent drug-related side effect.

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

DESCRIPTION

Carboplatin Injection is for intravenous administration. Each mL contains equivalent to 10 mg of carboplatin in Water for Injection. No other preservatives or additives are present. The aqueous solution is sterile and nonpyrogenic. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutane-dicarboxylato(2-)-0,0']-,(SP-4-2), and carboplatin has the following structural formula:

Chemical Structure
(click image for full-size original)

Carboplatin is a crystalline powder with the molecular formula of C6 H12 N2 O4 Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

CLINICAL PHARMACOLOGY

Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates.

In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 500 mg/m2).

Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days.

The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs.

In patients with creatinine clearances below 60 mL/min the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION).

The primary determinant of carboplatin clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR (see DOSAGE AND ADMINISTRATION) to provide predictable carboplatin plasma AUCs should be used in elderly patients to minimize the risk of toxicity.

CLINICAL STUDIES

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 cyclophosphamide every 28 days for 6 courses before surgical reevaluation. The following results were obtained from both studies:

Comparative Efficacy

Overview of Pivitol Trials
NCIC SWOG

Number of patients randomized

447

342

Median age (years)

60

62

Dose of cisplatin

75 mg/m2

100 mg/m2

Dose of carboplatin

300 mg/m2

300 mg/m2

Dose of cyclophosphamide

600 mg/m2

600 mg/m2

Residual tumor <2 cm (number of patients)

39% (174/447)

14% (49/342)

Clinical Response in Measurable Disease Patients
NCIC SWOG

Carboplatin (number of patients)

60% (48/80)

58% (48/83)

Cisplatin (number of patients)

58% (49/85)

43% (33/76)

95% C.I. of difference(Carboplatin – Cisplatin)

(-13.9%, 18.6%)

(-2.3%, 31.1%)

Pathologic Complete Response *
NCIC SWOG
*
114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study

Carboplatin (number of patients)

11% (24/224)

10% (17/171)

Cisplatin (number of patients)

15% (33/223)

10% (17/171)

95% C.I. of difference(Carboplatin – Cisplatin)

(-10.7%, 2.5%)

(-6.9%, 6.9%)

Progression-Free Survival (PFS)
NCIC SWOG
*
Kaplan-Meier EstimatesUnrelated deaths occuring 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.

Median

Carboplatin

59 weeks

49 weeks

Cisplatin

61 weeks

47 weeks

2-year PFS *

Carboplatin

31%

21%

Cisplatin

31%

21%

95% C.I. of difference(Carboplatin – Cisplatin)

(-9.3, 8.7)

(-9, 9.4)

3-year PFS *

Carboplatin

19%

8%

Cisplatin

23%

14%

95% C.I. of difference(Carboplatin – Cisplatin)

(-11.5, 4.5)

(-14.1, 0.3)

Hazard Ratio

1.10

1.02

95% C.I.(Carboplatin – Cisplatin)

(0.89, 1.35)

(0.81, 1.29)

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

Median

Carboplatin

110 weeks

86 weeks

Cisplatin

99 weeks

79 weeks

2-year Survival*

Carboplatin

51.9%

40.2%

Cisplatin

48.4%

39%

95% C.I. of difference(Carboplatin – Cisplatin)

(-6.2, 13.2)

(-9.8, 12.2)

3-year Survival*

Carboplatin

34.6%

18.3%

Cisplatin

33.1%

24.9%

95% C.I. of difference(Carboplatin – Cisplatin)

(-7.7, 10.7)

(-15.9, 2.7)

Hazard Ratio *

0.98

1.01

95% C.I.(Carboplatin – Cisplatin)

(0.78, 1.23)

(0.78, 1.30)

* Kaplan-Meier Estimates

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