Carboplatin

CARBOPLATIN — carboplatin injection, solution
Fresenius Kabi USA, LLC

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 supplied as a sterile, pyrogen-free solution available in 10 mg per mL multiple dose vials containing 50 mg, 150 mg, 450 mg or 600 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:

structure

C 6 H 12 N 2 O 4 Pt 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.

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 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 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 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 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 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 cyclophos-phamide 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/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)
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
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.

Progression-Free Survival (PFS)
NCIC SWOG
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) (-9.0, 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)

*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.

Survival
NCIC SWOG
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**
95% C.I. 0.98 1.01
(Carboplatin-Cisplatin) (0.78, 1.23) (0.78, 1.30)

*Kaplan-Meier Estimates

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

Comparative Toxicity

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 NCIC STUDY
Carboplatin Arm Percent * Cisplatin Arm Percent * P-Values **
Bone Marrow
Thrombocytopenia
< 100,000/mm 3 70 29 <0.001
< 50,000/mm 3 41 6 <0.001
Neutropenia
< 2,000 cells/mm 3 97 96 n.s.
< 1,000 cells/mm 3 81 79 n.s.
Leukopenia
< 4,000 cells/mm 3 98 97 n.s.
< 2,000 cells/mm 3 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 0.010
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 10 n.s.
Alopecia+ 50 62 0.017
Mucositis 10 9 n.s.

*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
Carboplatin Arm Percent* Cisplatin Arm Percent* P-Values**
Bone Marrow
Thrombocytopenia
< 100,000/mm 3 59 35 <0.001
<50,000/mm 3 22 11 0.006
Neutropenia
< 2,000 cells/mm 3 95 97 n.s.
< 1,000 cells/mm 3 84 78 n.s.
Leukopenia
< 4,000 cells/mm 3 97 97 n.s.
< 2,000 cells/mm 3 76 67 n.s.
Anemia
< 11 g/dL 88 87 n.s.
< 8 g/dL 8 24 < 0.001
Infections 18 21 n.s.
Bleeding 6 4 n.s.
Transfusions 25 33 n.s.
Gastrointestinal
Nausea and vomiting 94 96 n.s.
Vomiting 82 91 0.007
Other GI side effects 40 48 n.s.
Neurologic
Peripheral neuropathies 13 28 0.001
Ototoxicity 12 30 <0.001
Other sensory side effects 4 6 n.s.
Central neurotoxicity 23 29 n.s.
Renal
Serum creatinine elevations 7 38 <0.001
Blood urea elevations
Hepatic
Bilirubin elevations 5 3 n.s.
SGOT elevations 23 16 n.s.
Alkaline phosphatase elevations 29 20 n.s.
Electrolytes loss
Sodium
Potassium
Calcium
Magnesium 58 77 <0.001
Other side effects
Pain 54 52 n.s.
Asthenia 43 46 n.s.
Cardiovascular 23 30 n.s.
Respiratory 12 11 n.s.
Allergic 10 11 n.s.
Genitourinary 11 13 n.s.
Alopecia+ 43 57 0.009
Mucositis 6 11 n.s.

*Values are in percent of evaluable patients.

**n.s.= not significant, p>0.05.

+May have been affected by cyclophosphamide dosage delivered.

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