PARAPLATIN- carboplatin injection
Accord BioPharma Inc.
Paraplatin ® (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 Paraplatin ® administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.
Paraplatin ® injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin, USP. Carboplatin, USP is a platinum coordination compound. The chemical name for carboplatin, USP is platinum, diammine [1,1-cyclobutanedicarboxylato(2-)- O,O’ ]-,(SP-4-2), and carboplatin, USP has the following structural formula:
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 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.
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/m 2 to 500 mg/m 2 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 C max 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/m 2 to 500 mg/m 2).
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 Paraplatin ® 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 Paraplatin ® plasma AUCs should be used in elderly patients to minimize the risk of toxicity.
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:
|Number of patients randomized||447||342|
|Median age (years)||60||62|
|Dose of cisplatin||75 mg/m 2||100 mg/m 2|
|Dose of carboplatin||300 mg/m 2||300 mg/m 2|
|Dose of cyclophosphamide||600 mg/m 2||600 mg/m 2|
|Residual tumor < 2 cm (number of patients)||39% (174/447)||14% (49/342)|
|Carboplatin (number of patients)||60% (48/80)||58% (48/83)|
|Cisplatin (number of patients)||58% (49/85)||43% (33/76)|
|95% CI of difference (Carboplatin-Cisplatin)||(-13.9%, 18.6%)||(-2.3%, 31.1%)|
|Carboplatin (number of patients)||11% (24/224)||10% (17/171)|
|Cisplatin (number of patients)||15% (33/223)||10% (17/171)|
|95% CI of difference (Carboplatin-Cisplatin)||(-10.7%, 2.5%)||(-6.9%, 6.9%)|
|Carboplatin||59 weeks||49 weeks|
|Cisplatin||61 weeks||47 weeks|
|2-year PFS *|
|95% CI of difference (Carboplatin-Cisplatin)||(-9.3, 8.7)||(-9.0, 9.4)|
|3-year PFS *|
|95% CI of difference (Carboplatin-Cisplatin)||(-11.5, 4.5)||(-14.1, 0.3)|
|Hazard Ratio †||1.10||1.02|
|95% CI (Carboplatin-Cisplatin)||(0.89, 1.35)||(0.81, 1.29)|
|Carboplatin||110 weeks||86 weeks|
|Cisplatin||99 weeks||79 weeks|
|2-year Survival *|
|95% CI of difference (Carboplatin-Cisplatin)||(-6.2, 13.2)||(-9.8, 12.2)|
|3-year Survival *|
|95% CI of difference (Carboplatin-Cisplatin)||(-7.7, 10.7)||(-15.9, 2.7)|
|Hazard Ratio †|
|(Carboplatin–Cisplatin)||(0.78, 1.23)||(0.78, 1.30)|
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