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CARBOplatin for Injection USP | Carboplatin

13:58 EDT 24th July 2014 | BioPortfolio

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WARNING

Carboplatin for 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.

Carboplatin for Injection USP is supplied as a sterile, lyophilized white powder available in single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin for administration by intravenous infusion. Each vial contains equal parts by weight carboplatin and mannitol.

Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutane-dicarboxylato(2-)-0,0’]-, (SP-4-2), and has the following structural formula:

Carboplatin is a crystalline powder with the molecular formula of CHNOPt 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.

IMAGE 09c029ae-17a0-43e7-a1b0-58d066d34f53-01.jpg

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 to 500 mg/m of carboplatin. 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 are 4.4 L/hour, 16 L and 3.5 hours, respectively. The C 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, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 to 500 mg/m ).

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 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.

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 six 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 300 mg/m2 300 mg/m2
Dose of cyclosphosphamide 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 Response114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study
90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study
NCIC SWOG
Carboplatin (number of patents) 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)
Median NCIC SWOG 3-year PFSKaplan-Meier Estimates
Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis.
NCIC SWOG
Carboplatin 59 weeks 49 weeks Carboplatin 19% 8%
Cisplatin 61 weeks 47 weeks Cisplatin 23% 14%
2-year PFS 95% C.I. of difference
Carboplatin 31% 21% (Carboplatin - Cisplatin) (-11.5,4.5) (-14.1,0.3)
Cisplatin 31% 21% Hazard RatioAnalysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
95% C.I. of difference 95% C.I. 1.10 1.02
(Carboplatin - Cisplatin) (-9.3,8.7) (-9.0,9.4) (Carboplatin - Cisplatin) (0.89,1.35) (0.81,1.29)
Survival
Median NCIC SWOG 3-year SurvivalKaplan-Meier Estimates NCIC SWOG
Carboplatin 110 weeks 86 weeks Carboplatin 34.6% 18.3%
Cisplatin 99 weeks 79 weeks Cisplatin 33.1% 24.9%
2-year Survival 95% C.I. of difference
Carboplatin 51.9% 40.2% (Carboplatin - Cisplatin) (-7.7,10.7) (-15.9, 2.7)
Cisplatin 48.4% 39.0% Hazard RatioAnalysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
95% C.I. of difference 95% C.I. 0.98 1.01
(Carboplatin - Cisplatin) (-6.2,13.2) (-9.8,12.2) (Carboplatin - Cisplatin) (0.78,1.23) (0.78,1.30)

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

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY
Carboplatin Arm PercentValues are in percent of evaluable patients Cisplatin Arm Percent P-Valuesn.s.= not significant, p>0.05 Carboplatin Arm Percent Cisplatin Arm Percent P-Values
Bone Marrow Renal
Thrombocytopenia <100,000/mm3 70 29 <0.001 Serum creatinine elevations 5 13 0.006
<50,000/ mm3 41 6 <0.001 Blood urea elevations 17 31 <0.001
Neutropenia <2000 cells/ mm3 97 96 n.s. Hepatic
<1000 cells/ mm3 81 79 n.s. Bilirubin elevations 5 3 n.s.
Leukopenia <4000 cells/ mm3 98 97 n.s SGOT elevations 17 13 n.s.
<2000 cells/ mm3 68 52 0.001 Alkaline phosphatase elevations
Anemia <11 g/dL 91 91 n.s. Electrolytes loss
<8 g/dL 18 12 n.s. Sodium 10 20 0.005
Infections 14 12 n.s. Potassium 16 22 n.s.
Bleeding 10 4 n.s. Calcium 16 19 n.s.
Transfusions 42 31 0.018 Magnesium 63 88 <0.001
Gastrointestinal Other side effects
Nausea and vomiting 93 98 0.010 Pain 36 37 n.s.
Vomiting 84 97 <0.001 Asthenia 40 33 n.s.
Other GI side effects 50 62 0.013 Cardiovascular 15 19 n.s.
Neurologic Respiratory 8 9 n.s.
Peripheral neuropathies 16 42 <0.001 Allergic 12 9 n.s.
Ototoxicity 13 33 <0.001 Genitourinary 10 10 n.s.
Other sensory side effects 6 10 n.s. AlopeciaMay have been affected by cyclophosphamide dosage delivered 50 62 0.017
Central neurotoxicity 28 40 0.009 Mucositis 10 9 n.s.
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
Carboplatin Arm PercentValues are in percent of evaluable patients Cisplatin Arm Percent P-Valuesn.s.= not significant, p>0.05 Carboplatin Arm Percent Cisplatin Arm Percent P-Values
Bone Marrow Renal
Thrombocytopenia <100,000/mm3 59 35 <0.001 Serum creatinine elevations 7 38 <0.001
<50,000/ mm3 22 11 0.006 Blood urea elevations
Neutropenia <2000 cells/ mm3 95 97 n.s. Hepatic
<1000 cells/ mm3 84 78 n.s. Bilirubin elevations 5 3 n.s.
Leukopenia <4000 cells/ mm3 97 97 n.s SGOT elevations 23 16 n.s.
<2000 cells/ mm3 76 67 n.s. Alkaline phosphatase elevations 29 20 n.s.
Anemia <11 g/dL 88 87 n.s. Electrolytes loss
<8 g/dL 8 24 <0.001 Sodium
Infections 18 21 n.s. Potassium
Bleeding 6 4 n.s. Calcium
Transfusions 25 33 n.s. Magnesium 58 77 <0.001
Gastrointestinal Other side effects
Nausea and vomiting 94 96 n.s. Pain 54 52 n.s.
Vomiting 82 91 0.007 Asthenia 43 46 n.s.
Other GI side effects 40 48 n.s. Cardiovascular 23 30 n.s.
Neurologic Bedford Laboratories

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