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All about: Carboplatin

Big Image Dosage Form: Injection

Rx ONLY

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 Description

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 C6H12N2O4Pt 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.

Carboplatin - 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/m2 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 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, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 to 500 mg/m2 ).

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.

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 cyclophosphamide every 28 days for six courses before surgical reevaluation. The following results were obtained from both studies:

COMPARATIVE EFFICACY
*
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
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 Response*
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%)
*
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.
Progression-Free Survival (PFS)
Median NCIC SWOG 3-year PFS* 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 Ratio
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)
*
Kaplan-Meier Estimates
Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Survival
Median NCIC SWOG 3-year Survival* 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 Ratio
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)

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 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
Carboplatin Arm Percent* Cisplatin Arm Percent * P-Values 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. Alopecia 50 62 0.017
Central neurotoxicity 28 40 0.009 Mucositis 10 9 n.s.
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 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 Respiratory 12 11 n.s.
Peripheral neuropathies 13 28 0.001 Allergic 10 11 n.s.
Ototoxicity 12 30 <0.001 Genitourinary 11 13 n.s.
Other sensory side effects 4 6 n.s. Alopecia 43 57 0.009
Central neurotoxicity 23 29 n.s. Mucositis 6 11 n.s.

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

In two prospective, randomized controlled studies in patients with advanced ovarian cancer previously treated with chemotherapy, Carboplatin for injection achieved six clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71+ weeks.

Indications and Usage for Carboplatin

Initial Treatment of Advanced Ovarian Carcinoma

Carboplatin is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of Carboplatin and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with Carboplatin vs. cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES section).

There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and longterm survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.

Secondary Treatment of Advanced Ovarian Carcinoma

Carboplatin is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.

Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.

Contraindications

Carboplatin is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds.

Carboplatin should not be employed in patients with severe bone marrow depression or significant bleeding.

Warnings

Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during Carboplatin treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single-agent Carboplatin. In general, single intermittent courses of Carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered.

Since anemia is cumulative, transfusions may be needed during treatment with Carboplatin, particularly in patients receiving prolonged therapy.

Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial Carboplatin dosages in these patients should be appropriately reduced (see DOSAGE AND ADMINISTRATION) and blood counts should be carefully monitored between courses. The use of Carboplatin in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects.

Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when Carboplatin was administered at higher than recommended doses in combination with other ototoxic agents.

Carboplatin can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of Carboplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over five consecutive daily pulse doses has resulted in reduced emesis.

Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving Carboplatin as secondary treatment.

Loss of vision, which can be complete for light and colors, has been reported after the use of Carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.

As in the case of other platinum coordination compounds, allergic reactions to Carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions.)

High dosages of Carboplatin (more than four times the recommended dose) have resulted in severe abnormalities of liver function tests.

Carboplatin may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

General

Needles or intravenous administration sets containing aluminum parts that may come in contact with Carboplatin should not be used for the preparation or administration of the drug. Aluminum can react with Carboplatin causing precipitate formation and loss of potency.

Drug Interactions

The renal effects of nephrotoxic compounds may be potentiated by Carboplatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy.

Pregnancy

Teratogenic Effects; Pregnancy Category D:

(see WARNINGS).

Nursing Mothers

It is n

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