CARBOPLATIN injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
CARBOPLATIN (UNII: BG3F62OND5) (CARBOPLATIN - UNII:BG3F62OND5)
Available from:
Accord Healthcare, Inc.
INN (International Name):
CARBOPLATIN
Composition:
CARBOPLATIN 10 mg in 1 mL
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Carboplatin injection 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 versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES ). There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term 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. Carboplatin injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been
Product summary:
Each mL of carboplatin injection contains 10 mg of carboplatin, USP in water for injection and is available in individual cartons as follows: Unopened vials of carboplatin injection are stable to the date indicated on the package when stored at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. PROTECT FROM LIGHT. Carboplatin injection multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25°C following multiple needle entries. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Solutions for infusion should be discarded 8 hours after preparation. Caution  should be exercised in handling and preparing carboplatin injection. Several guidelines on this subject have been published. 1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing carboplatin injection. If carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.
Authorization status:
Abbreviated New Drug Application
Authorization number:
16729-295-12, 16729-295-31, 16729-295-33, 16729-295-34, 16729-295-38

CARBOPLATIN- carboplatin injection

Accord Healthcare, Inc.

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CARBOplatin Injection

Rxonly

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 injection administration. Epinephrine, corticosteroids, and antihistamines have been

employed to alleviate symptoms.

DESCRIPTION

Carboplatin 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-)-0,0']-,(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.

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 mg/m

to 500 mg/m

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

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

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 injection 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

injection 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 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

Median age (years)

Dose of cisplatin

75 mg/m

100 mg/m

Dose of carboplatin

300 mg/m

300 mg/m

Dose of cyclophosphamide

600 mg/m

600 mg/m

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% CI 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% CI of difference

(Carboplatin-Cisplatin)

(-10.7%, 2.5%)

(-6.9%, 6.9%)

Progression-Free Survival (PFS)

NCIC

SWOG

Median

Carboplatin

59 weeks

49 weeks

Cisplatin

61 weeks

47 weeks

2-year PFS

Carboplatin

Cisplatin

95% CI of difference

(Carboplatin-Cisplatin)

(-9.3, 8.7)

(-9, 9.4)

3-year PFS

Carboplatin

Cisplatin

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)

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%

95% CI 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% CI of difference

(Carboplatin-Cisplatin)

(-7.7, 10.7)

(-15.9, 2.7)

Hazard Ratio

*

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.

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.

95% CI

0.98

1.01

(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

Carboplatin

Percent

Cisplatin

Percent

P-Values

Bone Marrow

Thrombocytopenia <100,000/mm70

<0.001

<50,000/mm 41

<0.001

Neutropenia

<2,000

cells/mm

<1,000

cells/mm

Leukopenia

<4,000

cells/mm

<2,000

cells/mm

0.001

Anemia

<11 g/dL

<8 g/dL

Infections

Bleeding

Transfusions

0.018

Gas trointes tinal

Nausea and

vomiting

0.010

Vomiting

<0.001

Other GI side

effects

0.013

Neurologic

Peripheral

<0.001

Kaplan-Meier Estimates

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

neuropathies

Ototoxicity

<0.001

Other sensory side

effects

Central

neurotoxicity

0.009

Renal

Serum creatinine

elevations

0.006

Blood urea

elevations

<0.001

Hepatic

Bilirubin

elevations

SGOT elevations

Alkaline

phosphatase

elevations

Electrolytes loss

Sodium

0.005

Potassium

Calcium

Magnesium

<0.001

Other side effects

Pain

Asthenia

Cardiovascular

Respiratory

Allergic

Genitourinary

Alopecia

0.017

Mucositis

ADVERSE EXPERIENCES IN PATIENTS WITH

OVARIAN CANCER SWOG STUDY

Carboplatin

Percent

Cisplatin

Percent

P-Values

Bone Marrow

Thrombocytopenia <100,000/mm59

<0.001

<50,000/mm 22

0.006

Neutropenia

<2,000

cells/mm

Values are in percent of evaluable patients

ns = not significant, p>0.05

May have been affected by cyclophosphamide dosage delivered

<1,000

cells/mm

Leukopenia

<4,000

cells/mm

<2,000

cells/mm

Anemia

<11 g/dL

<8 g/dL

<0.001

Infections

Bleeding

Transfusions

Gas trointes tinal

Nausea and

vomiting

Vomiting

0.007

Other GI side

effects

Neurologic

Peripheral

neuropathies

0.001

Ototoxicity

<0.001

Other sensory side

effects

Central

neurotoxicity

Renal

Serum creatinine

elevations

<0.001

Blood urea

elevations

Hepatic

Bilirubin

elevations

SGOT elevations

Alkaline

phosphatase

elevations

Electrolytes loss

Sodium

Potassium

Calcium

Magnesium

<0.001

Other side effects

Pain

Asthenia

Cardiovascular

Respiratory

Allergic

Genitourinary

Alopecia

0.009

Mucositis

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 achieved 6 clinical complete responses in 47 patients. The

duration of these responses ranged from 45 to 71+ weeks.

INDICATIONS

Initial Treatment of Advanced Ovarian Carcinoma

Carboplatin injection 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 versus cisplatin, both in combination with cyclophosphamide, have

demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES).

There is limited statistical power to demonstrate equivalence in overall pathologic complete response

rates and long-term 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 injection 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 injection is contraindicated in patients with a history of severe allergic reactions to cisplatin

or other platinum-containing compounds.

Carboplatin injection 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 injection 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

Values are in percent of evaluable patients

ns = not significant, p>0.05

May have been affected by cyclophosphamide dosage delivered

function. Initial carboplatin injection 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 4 times the recommended dose) have resulted in severe

abnormalities of liver function tests.

Carboplatin injection 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 injection 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

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity

in nursing infants secondary to carboplatin treatment of the mother, it is recommended that breastfeeding

be discontinued if the mother is treated with carboplatin injection.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see WARNINGS, "audiologic

toxicity").

Geriatric Use

Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were

treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of

age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms

of safety, elderly patients treated with carboplatin were more likely to develop severe

thrombocytopenia than younger patients. In a combined database of 1,942 patients (414 were ≥ 65 years

of age) that received single agent carboplatin for different tumor types, a similar incidence of adverse

events was seen in patients 65 years and older and in patients less than 65. Other reported clinical

experience has not identified differences in responses between elderly and younger patients, but greater

sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in

the elderly, renal function should be considered in the selection of carboplatin injection dosage (see

DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

For a comparison of toxicities when carboplatin or cisplatin was given in combination with

cyclophosphamide, see CLINICAL STUDIES, Use with Cyclophosphamide for Initial Treatment

of Ovarian Cancer, Comparative Toxicity.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER

First Line Combination

Therapy

Percent

Second Line Single

Agent Therapy

Percent

Bone Marrow

Thrombocytopenia

<100,000/mm

<50,000/mm

Neutropenia

<2,000 cells/mm

<1,000 cells/mm

Leukopenia

<4,000 cells/mm

<2,000 cells/mm

Anemia

<11 g/dL

<8g/dL

Infections

Bleeding

Transfusions

Gas trointes tinal

Nausea and vomiting

Vomiting

Other GI side effects

Neurologic

Peripheral neuropathies

Ototoxicity

Other sensory side effects

Central neurotoxicity

Renal

Serum creatinine elevations

Blood urea elevations

Hepatic

Bilirubin elevations

SGOT elevations

Alkaline phosphatase elevations

Electrolytes loss

Sodium

Potassium

Calcium

Magnesium

Other side effects

Pain

Asthenia

Cardiovascular

Respiratory

Allergic

Genitourinary

Alopecia

Mucositis

In the narrative section that follows, the incidences of adverse events are based on data from 1,893

patients with various types of tumors who received carboplatin as single agent therapy.

Hematologic Toxicity

Bone marrow suppression is the dose-limiting toxicity of carboplatin. Thrombocytopenia with platelet

counts below 50,000/mm

occurs in 25% of the patients (35% of pretreated ovarian cancer patients);

neutropenia with granulocyte counts below 1,000/mm

occurs in 16% of the patients (21% of

pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm

occurs in 15% of

the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Data are based on the experience of 393

patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with

carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see

CLINICAL STUDIES). Combination with cyclophosphamide as well as duration of treatment may be responsible

for the differences that can be noted in the adverse experience table.

Single Agent Use for the Secondary Treatment of Ovarian Cancer: Data are based on the experience of 553

patients with previously treated ovarian carcinoma (regardless of baseline status) who received single agent

carboplatin.

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