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CARBOPLATININJECTIONRx only | Carboplatin

12:55 EDT 24th July 2014 | BioPortfolio

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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.

Carboplatin Injection is supplied as a sterile, pyrogen-free solution available in 10 mg/mL multiple-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin for administration by intravenous infusion. Each mL contains: carboplatin 10 mg and water for injection to volume.

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 has the following structural formula:

 

 CHNOPt                                                                                              M.W. 371.25

Carboplatin 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.

IMAGE Carboplatinstructure.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 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.

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:

Overview of Pivotal Trials

Clinical Response in Measurable Disease Patients

Pathologic Complete Response*

Progression-Free Survival (PFS)

Survival

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)  
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%)
NCIC
SWOG
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%)
* 114 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.
Median
NCIC
SWOG
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**
1.1
1.02
95% C.I.
(Carboplatin - Cisplatin)
(0.89, 1.35)
(0.81, 1.29)
* 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.
Median
NCIC
SWOG
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, 1.3)
* Kaplan-Meier Estimates 
** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.

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

Values are in percent of evaluable patients n.s. = not significant, p > 0.05+  May have been affected by cyclophosphamide dosage delivered

 

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY

Values are in percent of evaluable patients n.s. = not significant, p > 0.05+  May have been affected by cyclophosphamide dosage delivered

 
Carboplatin
Arm
Percent*
Cisplatin
Arm
Percent*


P-Values**
Bone Marrow
  Thrombocytopenia
      <100,000/mm3
70
29
<0.001
      <50,000/mm3
41
6
<0.001
  Neutropenia
      <2,000 cells/mm3
97
96
n.s.
      <1,000 cells/mm3
81
79
n.s.
  Leukopenia
      <4,000 cells/mm3
98
97
n.s.
      <2,000 cells/mm3
68
52
0.001
  Anemia
      <11 g/dL
91
91
n.s.
      <8 g/dL
18
12
n.s.
  Infections
14
12
n.s.
  Bleeding
10
4
n.s.
  Transfusions
42
31
0.018
Gastrointestinal
  Nausea and vomiting
93
98
0.01
  Vomiting
84
97
<0.001
  Other GI side effects
50
62
0.013
Neurologic
  Peripheral neuropathies
16
42
<0.001
  Ototoxicity
13
33
<0.001
  Other sensory side effects
6
10
n.s.
  Central neurotoxicity
28
40
0.009
Renal
  Serum creatinine elevations
5
13
0.006
  Blood urea elevations
17
31
<0.001
Hepatic
  Bilirubin elevations
5
3
n.s.
  SGOT elevations
17
13
n.s.
  Alkaline phosphatase elevations
-
-
-
Electrolytes loss
  Sodium
10
20
0.005
  Potassium
16
22
n.s.
  Calcium
16
19
n.s.
  Magnesium
63
88
<0.001
Other side effects
  Pain
36
37
n.s.
  Asthenia
40
33
n.s.
  Cardiovascular
15
19
n.s.
  Respiratory
8
9
n.s.
  Allergic
12
9
n.s.
  Genitourinary
10
Manufacturer

APP Pharmaceuticals, LLC

Active Ingredients

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Clinical Trials [1197 Associated Clinical Trials listed on BioPortfolio]

Phase I Study of TAS-106 in Combo With Carboplatin

The goal of this clinical research study is to find the highest safe dose of the combination of TAS-106 and carboplatin that can be given to patients with advanced cancer or cancer that ha...

First Line Chemotherapy Treatment of Advanced NSCLC

The purposes of this study are to determine: The safety of enzastaurin plus pemetrexed with carboplatin, pemetrexed with carboplatin, or docetaxel with carboplatin and any side effects th...

Study of Pemetrexed and Carboplatin Compared With Etoposide Carboplatin to Treat Extensive-Stage Small Cell Lung Cancer

This study is a Phase 3, global, multi-center, open-label study of patients with extensive-stage small cell lung cancer. Eligible patients will be randomly assigned to receive either pemet...

Belinostat, Carboplatin and Paclitaxel (BelCaP) Compared to Carboplatin and Paclitaxel in Patients With Cancer of Unknown Primary

The purpose of this study is to assess efficacy and safety of belinostat in combination with carboplatin and paclitaxel in patients with previously untreated carcinoma of unknown primary.

E7080 in Combination With Carboplatin + Gemcitabine Versus Carboplatin + Gemcitabine Alone as Second Line Therapy in Patients With Platinum-Sensitive Recurrent Ovarian Cancer by CA125

The purpose of this study is to determine the MTD/recommended Phase II dose of E7080 administered in combination with carboplatin and gemcitabine (Phase IB) and to evaluate the safety and ...

PubMed Articles [72 Associated PubMed Articles listed on BioPortfolio]

Evaluation of calculating carboplatin dosage in carboplatin-pemetrexed therapy as the first-line therapy for Chinese patients with advanced lung adenocarcinoma.

This study aims to explore the application of actual carboplatin in carboplatin plus pemetrexed regimen as first-line treatment for advanced lung adenocarcinoma, and to determine the recommended dose ...

Experimental animal study of docetaxel combined with carboplatin in the treatment of retinoblastoma.

The synergistic effects of docetaxel (DTX) combined with carboplatin in the treatment of retinoblastoma (RB) was explored in mouse RB xenografts compared with carboplatin alone and DTX alone groups. R...

Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.

Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadju...

The FoxM1-ABCC4 axis mediates carboplatin resistance in human retinoblastoma Y-79 cells.

Carboplatin is the most commonly used drug in the first-line treatment of human retinoblastoma (RB), but its clinical application is greatly limited due to acquired drug resistance upon the long-term ...

Carboplatin as an alternative to Cisplatin in chemotherapies: New insights at single molecule level.

Here we report a new study performed at single molecule level on the interaction of the antineoplastic drug Carboplatin and the DNA molecule - the main target of the drug inside cells in cancer chemot...

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