Carboplatin

CARBOPLATIN- carboplatin solution
Sanja Pharmaceuticals Company

Package Insert

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, USP have been reported and may occur within minutes of carboplatin injection administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

DESCRIPTION

Carboplatin injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin, USP. Each mL contains 10 mg carboplatin, USP, 10 mg mannitol and water for injection, USP. Carboplatin, USP is a platinum coordination compound. The chemical name for carboplatin, USP is platinum, diammine [1,1-cyclobutane-dicarboxylato (2-)-0,0′]-, (SP-4-2), and carboplatin, USP has the following structural formula:

Molecule

C6 H12 N2 O4 Pt M.W. 371.25

Carboplatin, USP is a crystalline powder. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5–7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

CLINICAL PHARMACOLOGY

Carboplatin, USP, 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, USP, 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, USP and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin, USP 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, USP decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2 of carboplatin, USP. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (N=6), and the post distribution 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, USP is 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration vs time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, USP, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 500 mg/m2).

Carboplatin, USP is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin, USP are present in plasma. However, platinum from carboplatin, USP 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, USP 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, USP. 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, USP decrease as the creatinine clearance decreases. Carboplatin injection dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION).

The primary determinant of carboplatin injection 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 injection 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, USP 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 Pivotal 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, USP 300 mg/m2 100 mg/m2
Dose of cyclophosphamide 600 mg/m2 100 mg/m2
Residual tumor <2 cm (number of patients) 39% (174/342) 14% (49/342)
Clinical Response in Measurable Disease Patients
NCIC SWOG
Carboplatin, USP (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, USP — Cisplatin) (-13.9%, 18.6%) (-2.3%, 31.1%)
Pathologic Complete Response *
*
114 Carboplatin, USP and 109 Cisplatin patients did not undergo second look surgery in NCIC study 90 Carboplatin, USP and 106 Cisplatin patients did not undergo second look surgery in SWOG study
NCIC SWOG
Carboplatin, USP (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, USP — Cisplatin) (-10.7%, 2.5%) (-6.9%, 6.9%)
Progression-Free Survival (PFS)
*
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.
NCIC SWOG
Median
Carboplatin, USP 59 weeks 49 weeks
Cisplatin 61 weeks 47 weeks
2-year PFS *
Carboplatin, USP 31% 21%
Cisplatin 31% 21%
95% C.I. of difference (Carboplatin, USP -Cisplatin) (-9.3,8.7) (-9.0,9.4)
3-year PFS*
Carboplatin, USP 19% 8%
Cisplatin 23% 14%
95% C.I. of difference (Carboplatin, USP-Cisplatin) (-11.5, 4.5) (-14.1, 0.3)
Hazard Ratio 1.10 1.02
95% C.I. (Carboplatin, USP-Cisplatin) (0.89, 1.35) (0.81, 1.29)
Survival
*
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.
NCIC SWOG
Median
Carboplatin, USP 110 weeks 86 weeks
Cisplatin 99 weeks 79 weeks
2-year PFS *
Carboplatin, USP 51.90% 40.20%
Cisplatin 48.40% 39.00%
95% C.I. of difference (Carboplatin, USP-Cisplatin) (-6.2, 13.2) (-9.8, 12.2)
3-year PFS *
Carboplatin, USP 34.60% 18.30%
Cisplatin 33.10% 24.90%
95% C.I. of difference (Carboplatin, USP-Cisplatin) (-7.7, 10.7) (-15.9, 2.7)
Hazard Ratio 0.98 1.01
95% C.I. (Carboplatin, USP-Cisplatin) (0.78, 1.23) (0.78, 1.30)

Comparative Toxicity

The pattern of toxicity exerted by the carboplatin, USP-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, USP-containing regimen induced significantly more thrombocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatincontaining 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.

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