CARBOplatin

INJECTION
(aqueous solution)
Rx only

WARNING
Carboplatin injection (aqueous solution) 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 (aqueous solution) is supplied as a sterile, pyrogen-free, aqueous
solution available in 50 mg/5 mL, 150 mg/15 mL, or 450 mg/45 mL multidose vials
containing 10 mg/mL of carboplatin for administration by intravenous infusion. Each mL
contains 10 mg carboplatin, USP and Water for Injection, USP q.s.
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
carboplatin 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.

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 proteinfree,
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 section).
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
section) 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:
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 cyclophosphamide 600 mg/m2 600 mg/m2
Residual tumor < 2 cm 39% (174/447) 14% (49/342)
(number of patients)
 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 (-13.9%, 18.6%) (-2.3%, 31.1%)
(Carboplatin – Cisplatin)

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 (-10.7%, 2.5%) (-6.9%, 6.9%)
(Carboplatin – Cisplatin)
* 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 (-9.3, 8.7) (-9.0, 9.4)
(Carboplatin – Cisplatin)
3 year PFS*
Carboplatin 19% 8%
Cisplatin 23% 14%
95% C.I. of difference (-11.5, 4.5) (-14.1, 0.3)
(Carboplatin – Cisplatin)
Hazard Ratio** 1.10 1.02
95% C.I. (0.89, 1.35) (0.81, 1.29)
(Carboplatin – Cisplatin)
* 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
Median NCIC SWOG
Carboplatin 110 weeks 86 weeks
Cisplatin 99 weeks 79 weeks
2 year Survival*
Carboplatin 51.9% 40.2%
Cisplatin 48.4% 39.0%
95% C.I. of difference (-6.2, 13.2) (-9.8, 12.2)
(Carboplatin – Cisplatin)
3 year Survival*
Carboplatin 34.6% 18.3%
Cisplatin 33.1% 24.9%
95% C.I. of difference (-7.7, 10.7) (-15.9, 2.7)
(Carboplatin – Cisplatin)
Hazard Ratio** 0.98 1.01
95% C.I. (0.78, 1.23) (0.78, 1.30)
(Carboplatin – Cisplatin)
* 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 CANCER NCIC STUDY
Carboplatin Cisplatin
Arm Arm P-Values**
Percent* Percent*
Bone Marrow
Thrombocytopenia < 100,000/mm3 70 29 < 0. 001
< 50,000/mm3 41 6 < 0.001
Neutropenia < 2000 cells/mm3 97 96 ns
< 1000 cells/mm3 81 79 ns
Leukopenia < 4000 cells/mm3 98 97 ns
< 2000 cells/mm3 68 52 0.001
Anemia < 11 g/dL 91 91 ns
< 8 g/dL 18 12 ns
Infections 14 12 ns
Bleeding 10 4 ns
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 ns
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 ns
SGOT elevations 17 13 ns
Alkaline phosphatase elevations - - -
Electrolytes loss
Sodium 10 20 0.005
Potassium 16 22 ns
Calcium 16 19 ns
Magnesium 63 88 < 0.001
Other side effects
Pain 36 37 ns
Asthenia 40 33 ns
Cardiovascular 15 19 ns
Respiratory 8 9 ns
Allergic 12 9 ns
Genitourinary 10 10 ns
Alopecia+ 50 62 0.017
Mucositis 10 9 ns
* Values are in percent of evaluable patients.
** ns = not significant, p > 0.05.
+ May have been affected by cyclophosphamide dosage delivered.
 ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY
Carboplatin Cisplatin
Arm Arm
Percent* Percent* P-Values**
Bone Marrow
Thrombocytopenia < 100,000/mm3 59 35 < 0.001
< 50,000/mm3 22 11 0.006
Neutropenia < 2000 cells/mm3 95 97 ns
< 1000 cells/mm3 84 78 ns
Leukopenia < 4000 cells/mm3 97 97 ns
< 2000 cells/mm3 76 67 ns
Anemia < 11 g/dL 88 87 ns
< 8 g/dL 8 24 < 0.001
Infections 18 21 ns
Bleeding 6 4 ns
Transfusions 25 33 ns
Gastrointestinal
Nausea and vomiting 94 96 ns
Vomiting 82 91 0.007
Other GI side effects 40 48 ns
Neurologic
Peripheral neuropathies 13 28 0.001
Ototoxicity 12 30 < 0.001
Other sensory side effects 4 6 ns
Central neurotoxicity 23 29 ns
Renal
Serum creatinine elevations 7 38 < 0.001
Blood urea elevations - - -
Hepatic
Bilirubin elevations 5 3 ns
SGOT elevations 23 16 ns
Alkaline phosphatase elevations 29 20 ns
Electrolytes loss
Sodium - - -
Potassium - - -
Calcium - - -
Magnesium 58 77 < 0.001
Other side effects
Pain 54 52 ns
Asthenia 43 46 ns
Cardiovascular 23 30 ns
Respiratory 12 11 ns
Allergic 10 11 ns
Genitourinary 11 13 ns
Alopecia+ 43 57 0.009
Mucositis 6 11 ns
* Values are in percent of evaluable patients.
** ns = not significant, p > 0.05.
+ May have been affected by cyclophosphamide dosage delivered.

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 six clinical complete
responses in 47 patients. The duration of these responses ranged from 45 to 71 + weeks.

INDICATIONS AND USAGE

Initial Treatment of Advanced Ovarian Carcinoma: Carboplatin injection (aqueous
solution) 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 injection (aqueous solution) 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 section) 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 sections).
High dosages of carboplatin (more than four times the recommended dose) have
resulted in severe abnormalities of liver function tests.
Carboplatin injection (aqueous solution) 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 (aqueous solution) 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 section).
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 breast feeding be discontinued if the
mother is treated with carboplatin injection (aqueous solution).
Pediatric Use: Safety and effectiveness in pediatric patients have not been
established (see WARNINGS section; “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 1942 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 dosage (see DOSAGE AND
ADMINISTRATION section).

ADVERSE REACTIONS
For a comparison of toxicities when carboplatin or cisplatin was given in combination
with cyclophosphamide, see CLINICAL STUDIES section: Comparative Toxicity.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER

First Line Second Line
Combination Single Agent
Therapy* Therapy**
Percent Percent
Bone Marrow
Thrombocytopenia < 100,000/mm3 66 62
< 50,000/mm3 33 35
Neutropenia < 2000 cells/mm3 96 67
< 1000 cells/mm3 82 21
Leukopenia < 4000 cells/mm3 97 85
< 2000 cells/mm3 71 26
Anemia < 11 g/dL 90 90
< 8 g/dL 14 21
Infections 16 5
Bleeding 8 5
Transfusions 35 44
Gastrointestinal
Nausea and vomiting 93 92
Vomiting 83 81
Other GI side effects 46 21
Neurologic
Peripheral neuropathies 15 6
Ototoxicity 12 1
Other sensory side effects 5 1
Central neurotoxicity 26 5
Renal
Serum creatinine elevations 6 10
Blood urea elevations 17 22
Hepatic
Bilirubin elevations 5 5
SGOT elevations 20 19
Alkaline phosphatase elevations 29 37
Electrolytes loss
Sodium 10 47
Potassium 16 28
Calcium 16 31
Magnesium 61 43
 ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER
First Line Second Line
Combination Single Agent
Therapy* Therapy**
Percent Percent
Other side effects
Pain 44 23
Asthenia 41 11
Cardiovascular 19 6
Respiratory 10 6
Allergic 11 2
Genitourinary 10 2
Alopecia 49 2
Mucositis 8 1

* 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 section).
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.
In the narrative section that follows, the incidences of adverse events are based on data from 1893 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/mm3 occurs in 25% of
the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte
counts below 1000/mm3 occurs in 16% of the patients (21% of pretreated ovarian cancer
patients); leukopenia with WBC counts below 2000/mm3 occurs in 15% of the patients
(26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in
patients receiving single-agent therapy. By day 28, 90% of patients have platelet counts
above 100,000/mm3; 74% have neutrophil counts above 2000/mm3; 67% have leukocyte
counts above 4000/mm3.
Marrow suppression is usually more severe in patients with impaired kidney function.
Patients with poor performance status have also experienced a higher incidence of severe
leukopenia and thrombocytopenia.
The hematologic effects, although usually reversible, have resulted in infectious or
hemorrhagic complications in 5% of the patients treated with carboplatin, with drug
related death occurring in less than 1% of the patients. Fever has also been reported in
patients with neutropenia.
Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients
who started therapy with a baseline above that value. The incidence of anemia increases
with increasing exposure to carboplatin. Transfusions have been administered to 26% of
the patients treated with carboplatin (44% of previously treated ovarian cancer patients).
Bone marrow depression may be more severe when carboplatin is combined with
other bone marrow suppressing drugs or with radiotherapy.
Gastrointestinal Toxicity: Vomiting occurs in 65% of the patients (81% of
previously treated ovarian cancer patients) and in about one-third of these patients it is
severe. Carboplatin, as a single agent or in combination, is significantly less emetogenic
than cisplatin; however, patients previously treated with emetogenic agents, especially
cisplatin, appear to be more prone to vomiting. Nausea alone
occurs in an additional 10% to 15% of patients. Both nausea and vomiting usually cease
within 24 hours of treatment and are often responsive to antiemetic measures. Although
no conclusive efficacy data exist with the following schedules, prolonged administration
of carboplatin, either by continuous 24 hour infusion or by daily pulse doses given for 5
consecutive days, was associated with less severe vomiting than the single-dose
intermittent schedule. Emesis was increased when carboplatin was used in combination
with other emetogenic compounds. Other gastrointestinal effects observed frequently
were pain, in 17% of the patients; diarrhea, in 6%; and constipation, also in 6%.
Neurologic Toxicity: Peripheral neuropathies have been observed in 4% of the
patients receiving carboplatin (6% of pretreated ovarian cancer patients) with mild
paresthesias occurring most frequently. Carboplatin therapy produces significantly fewer
and less severe neurologic side effects than does therapy with cisplatin. However,
patients older than 65 years and/or previously treated with cisplatin appear to have an
increased risk (10%) for peripheral neuropathies. In 70% of the patients with pre-existing
cisplatin-induced peripheral neurotoxicity, there was no worsening of symptoms during
therapy with carboplatin. Clinical ototoxicity and other sensory abnormalities such as
visual disturbances and change in taste have been reported in only 1% of the patients.
Central nervous system symptoms have been reported in 5% of the patients and appear to
be most often related to the use of antiemetics.
Although the overall incidence of peripheral neurologic side effects induced by
carboplatin is low, prolonged treatment, particularly in cisplatin pretreated patients, may
result in cumulative neurotoxicity.
Nephrotoxicity: Development of abnormal renal function test results is uncommon,
despite the fact that carboplatin, unlike cisplatin, has usually been administered without
high-volume fluid hydration and/or forced diuresis. The incidences of abnormal renal
function tests reported are 6% for serum creatinine and 14% for blood urea nitrogen (10%
and 22%, respectively, in pretreated ovarian cancer patients). Most of these reported
abnormalities have been mild and about one-half of them were reversible.
Creatinine clearance has proven to be the most sensitive measure of kidney function
in patients receiving carboplatin, and it appears to be the most useful test for correlating
drug clearance and bone marrow suppression. Twenty-seven percent of the patients who
had a baseline value of 60 mL/min or more demonstrated a reduction below this value
during carboplatin therapy.
Hepatic Toxicity: The incidences of abnormal liver function tests in patients with
normal baseline values were reported as follows: total bilirubin, 5%; SGOT, 15%; and
alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated ovarian
cancer patients). These abnormalities have generally been mild and reversible in about
one-half of the cases, although the role of metastatic tumor in the liver may complicate
the assessment in many patients. In a limited series of patients receiving very high
dosages of carboplatin and autologous bone marrow transplantation, severe abnormalities
of liver function tests were reported.
Electrolyte Changes: The incidences of abnormally decreased serum electrolyte
values reported were as follows: sodium, 29%; potassium, 20%; calcium, 22%; and
magnesium, 29%; (47%, 28%, 31%, and 43%, respectively, in pretreated ovarian cancer
patients). Electrolyte supplementation was not routinely administered concomitantly with
carboplatin, and these electrolyte abnormalities were rarely associated with symptoms.
Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of the
patients. These allergic reactions have been similar in nature and severity to those
reported with other platinum-containing compounds, i.e., rash, urticaria, erythema,
pruritus, and rarely bronchospasm and hypotension. Anaphylactic reactions have been
reported as part of postmarketing surveillance (see WARNINGS section). These
reactions have been successfully managed with standard epinephrine, corticosteroid, and
antihistamine therapy.
Injection Site Reactions: Injection site reactions, including redness, swelling, and
pain, have been reported during postmarketing surveillance. Necrosis associated with
extravasation has also been reported.
Other Events: Pain and asthenia were the most frequently reported miscellaneous
adverse effects; their relationship to the tumor and to anemia was likely. Alopecia was
reported (3%). Cardiovascular, respiratory, genitourinary, and mucosal side effects have
occurred in 6% or less of the patients. Cardiovascular events (cardiac failure, embolism,
cerebrovascular accidents) were fatal in less than 1% of the patients and did not appear to
be related to chemotherapy. Cancer-associated hemolytic uremic syndrome has been
reported rarely.
Malaise, anorexia, and hypertension have been reported as part of postmarketing
surveillance.

OVERDOSAGE
There is no known antidote for carboplatin injection (aqueous solution) overdosage. The
anticipated complications of overdosage would be secondary to bone marrow suppression
and/or hepatic toxicity.

DOSAGE AND ADMINISTRATION

NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of
potency, therefore, needles or intravenous sets containing aluminum parts that may
come in contact with the drug must not be used for the preparation or
administration of carboplatin.

Single Agent Therapy: Carboplatin injection (aqueous solution) as a single agent,

has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage
of 360 mg/m2 I.V. on day 1 every 4 weeks (alternatively see Formula Dosing). In
general, however, single intermittent courses of carboplatin should not be repeated until
the neutrophil count is at least 2000 and the platelet count is at least 100,000.
Combination Therapy with Cyclophosphamide: In the chemotherapy of advanced
ovarian cancer, an effective combination for previously untreated patients consists of:
Carboplatin–300 mg/m2 I.V. on day 1 every four weeks for six cycles (alternatively
see Formula Dosing).
Cyclophosphamide–600 mg/m2 I.V. on day 1 every four weeks for six cycles. For
directions regarding the use and administration of cyclophosphamide please refer to its
package insert. (See CLINICAL STUDIES section).
Intermittent courses of carboplatin in combination with cyclophosphamide should not
be repeated until the neutrophil count is at least 2,000 and the platelet count is at least
100,000.
Dose Adjustment Recommendations: Pretreatment platelet count and performance
status are important prognostic factors for severity of myelosuppression in previously
treated patients.
The suggested dose adjustments for single agent or combination therapy shown in the
table below are modified from controlled trials in previously treated and untreated
patients with ovarian carcinoma. Blood counts were done weekly, and the
recommendations are based on the lowest post-treatment platelet or neutrophil value.
 Adjusted Dose *
Platelets Neutrophils (From Prior Course)
> 100,000 > 2000 125%
50 to 100,000 500 to 2000 No Adjustment
< 50,000 < 500 75%
*Percentages apply to carboplatin injection (aqueous solution) as a single agent or to both carboplatin and
cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%)
for severe myelosuppression. Escalations above 125% were not recommended for these studies.

Carboplatin is usually administered by an infusion lasting 15 minutes or longer. No

pre- or post-treatment hydration or forced diuresis is required.
Patients with Impaired Kidney Function: Patients with creatinine clearance values
below 60 mL/min are at increased risk of severe bone marrow suppression. In
renally-impaired patients who received single-agent carboplatin therapy, the incidence of
severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the
dosage modifications in the table below have been used.

Baseline Creatinine Recommended

Clearance Dose on Day 1
41 to 59 mL/min 250 mg/m2
16 to 40 mL/min 200 mg/m2

The data available for patients with severely impaired kidney function (creatinine
clearance below 15 mL/min) are too limited to permit a recommendation for treatment.
These dosing recommendations apply to the initial course of treatment. Subsequent
dosages should be adjusted according to the patient’s tolerance based on the degree of
bone marrow suppression.
Formula Dosing: Another approach for determining the initial dose of carboplatin is
the use of mathematical formulae, which are based on a patient’s pre-existing renal
function or renal function and desired platelet nadir. Renal excretion is the major route of
elimination for carboplatin. (See CLINICAL PHARMACOLOGY section). The use of
dosing formulae, as compared to empirical dose calculation based on body surface area,
allows compensation for patient variations in pretreatment renal function that might
otherwise result in either underdosing (in patients with above average renal function) or
overdosing (in patients with impaired renal function).
A simple formula for calculating dosage, based upon a patient’s glomerular filtration
rate (GFR in mL/min) and carboplatin target area under the concentration versus time
curve (AUC in mg/mL_min), has been proposed by Calvert. In these studies, GFR was
measured by 51Cr-EDTA clearance.
CALVERT FORMULA FOR CARBOPLATIN DOSING

Total Dose (mg)=(target AUC) x (GFR + 25)

Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.

The target AUC of 4 to 6 mg/ mL_min using single-agent carboplatin appears to

provide the most appropriate dose range in previously treated patients. This study also
showed a trend between the AUC of single-agent carboplatin administered to previously
treated patients and the likelihood of developing toxicity.
% Actual Toxicity in Previously Treated Patients
Gr 3 or Gr 4 Gr 3 or Gr 4
AUC (mg/mL_min) Thrombocytopenia Leukopenia
4 to 5 16% 13%
6 to 7 33% 34%

Geriatric Dosing: Because renal function is often decreased in elderly patients,

formula dosing of carboplatin based on estimates of GFR should be used in elderly
patients to provide predictable plasma carboplatin AUCs and thereby minimize the risk of
toxicity.

PREPARATION OF INTRAVENOUS SOLUTIONS

Carboplatin injection (aqueous solution) is a premixed aqueous solution of 10 mg/mL
carboplatin.
Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5
mg/mL with 5% Dextrose in Water (D5 W) or 0.9% Sodium Chloride Injection, USP.
When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at
room temperature (25 °C). Since no antibacterial preservative is contained in the
formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours
after dilution.

HOW SUPPLIED

Carboplatin injection (aqueous solution)

NDC 0409-1129-10 50 mg/5 mL aqueous solution in multidose vials (with
white flip-off seals), individually cartoned.

NDC 0409-1129-11 150 mg/15 mL aqueous solution in multidose vials (with

white flip-off seals), individually cartoned.

NDC 0409-1129-12 450 mg/45 mL aqueous solution in multidose vials (with

white flip-off seals), individually cartoned.

Storage
Unopened vials of Carboplatin injection (aqueous solution) are stable to the date
indicated on the package when stored at 25 °C (77 °F); excursions permitted from 15 °C
to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Protect from light.
Carboplatin injection (aqueous solution) 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.
Handling and Disposal
Procedures for proper handling and disposal of anti-cancer drugs should be
considered. Several guidelines on this subject have been published.1-7 There is no general
agreement that all of the procedures recommended in the guidelines are necessary or
appropriate.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH

Publication No. 83-2621. For sale by the Superintendent of Documents, US
Government Printing Office, Washington, DC 20402.
2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA
1985; 253(11):1590-1592.
3. National Study Commission on Cytotoxic Exposure–Recommendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D. Chairman, National Study
Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe
Handling of Antineoplastic Agents. Med J Australia 1983; 1:426–428.
5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. C A–A Cancer Journal for Clinicians 1983;
(Sept/Oct)258–263.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling
Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033–1049.
7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE
GUIDELINES). Am J Health-Syst Pharm 1996;53:1669-1685.

Manufactured By:
DABUR ONCOLOGY Plc.
Bordon, Hampshire GU35 0NF, UK

Distributed By:
HOSPIRA Worldwide, Inc.
Lake Forest, IL 60045, USA

EN-0869

Revised : August 2005

220002
 Rx only
O
Patient
Information
CARBOplatin Injection
(aqueous solution)

Read this entire leaflet carefully.

Keep it for future reference.

This information will help you learn more about Carboplatin Injection (aqueous solution).
It cannot, however, cover all the possible warnings or side effects relating to carboplatin,
and it does not list all of the benefits and risks of carboplatin. Your doctor should always
be your first choice for detailed information about your medical condition and your
treatment. Be sure to ask your doctor about any questions you may have.

What is cancer?
Under normal conditions, the cells in your body divide and grow in an orderly, controlled
fashion. Cell division and growth are necessary for the human body to perform its
functions and to repair itself. Cancer cells are different from normal cells because they
are not able to control their own
growth. The reasons for this abnormal growth are not yet fully understood.

A tumor is a mass of unhealthy cells that are dividing and growing fast and in an
uncontrolled way. When a tumor invades surrounding healthy body tissue it is known as
a malignant tumor. A malignant tumor can spread (metastasize) from its original location
to other parts of the body.

What is Carboplatin?
Carboplatin is a medicine that is used to treat cancer of the ovaries. It acts by interfering
with the division of rapidly multiplying cells, particularly cancer cells.

Who should not take Carboplatin?

Treatment with carboplatin is not recommended if you:
• are allergic to carboplatin or other platinum-containing products;
• have a weakened blood-forming system (bone marrow depression) or significant
bleeding;
• are pregnant, intend to become pregnant, or are breast-feeding a baby.

How is Carboplatin used?

Only a professional experienced in the use of cancer drugs should give you this
medication. Carboplatin is given by dripping the medicine slowly and directly into a vein
(intravenous infusion) for 15 minutes or longer. Your doctor will determine the dose of
carboplatin for you based on your weight, height, and kidney function. Carboplatin may
be given alone or with other drugs. Treatment is usually repeated every four weeks for a
number of cycles.
Before and after carboplatin treatment, your doctor may give you medication to lessen the
nausea and vomiting associated with this cancer treatment.

What should you tell your doctor before starting treatment with Carboplatin?
Discuss the benefits and risks of carboplatin with your doctor before beginning treatment.
Be sure to inform your doctor:
• If you are allergic to carboplatin or other platinum-containing products;
• If you are or intend to become pregnant, since carboplatin may harm the developing
fetus. It is important to use effective birth control while you are being treated with
carboplatin;
• If you are breast-feeding, since nursing infants may be exposed to carboplatin in this
way;
• If you are taking other medicines, including all prescription and non-prescription
(over-the-counter) drugs, since carboplatin may affect the action of other medicines;
• If you have any other medical problems, especially chicken pox (including recent
exposure to adults or children with chicken pox), shingles, hearing problems,
infection, or kidney disease, since treatment with carboplatin increases the risk and
severity of these conditions.

What should I avoid while taking Carboplatin?

If you are pregnant or think you might be pregnant, or if you are breast-feeding, let your
doctor know right away. Carboplatin may harm your developing fetus or breast-feeding
baby. If you are a woman of childbearing age, you should use birth control to avoid
getting pregnant while you are taking carboplatin.
You should avoid contact with adults and children who have infections, and tell your
doctor right away if you show signs of infection such as cough, fever, and/or chills. Also,
while you are being treated with carboplatin or after you stop treatment, first check with
your doctor before getting any immunizations (vaccinations). Avoid contact with adults
or children who have received oral polio vaccine since they can pass the polio virus to
you.

What are the possible side effects of Carboplatin?

Carboplatin may cause unwanted effects, particularly because carboplatin interferes with
the growth of normal cells as well as cancer cells. For example, the occurrence of another
cancer (secondary malignancy) has been reported in patients receiving cancer
chemotherapy with multiple drugs. It is not always possible to tell whether such effects
are caused by carboplatin, another drug you may be taking, or your illness. Because some
of these effects may be serious, you will need close medical supervision during treatment
with carboplatin.
The most serious side effects of carboplatin are:
• bleeding and reduced blood cells, including reduced red blood cells (anemia) and
platelets (needed for proper blood clotting), which may be severe enough to
require blood transfusion. You should tell your doctor right away if you notice any
unusual bruising or bleeding, including black tarry stools or blood in the urine.
• infection - carboplatin can temporarily lower the number of white blood cells in your
blood, increasing the risk of infection;
• life-threatening allergic reaction - during and after treatment the doctor or nurse
will observe you carefully for signs of allergic reaction;
• kidney and liver problems;
• loss of hearing or ringing in the ears;
Contact your doctor right away if you experience any of these effects,
or notice effects that worry you or are troublesome.
Of the less serious side effects associated with carboplatin treatment, the most common
are nausea, vomiting, diarrhea, loss of appetite, hair loss and numbness, tingling, burning,
or pain in the hands or feet.
________________________________________________________________________
______
This medicine was prescribed for your particular condition. It must be given under close medical
supervision by a doctor trained in the use of drugs for the treatment of cancer.

This summary does not include everything there is to know about carboplatin. Medicines are sometimes
prescribed for purposes other than those listed in patient leaflets. If you have questions or concerns, or want
more information about carboplatin, your physician and pharmacist have the complete prescribing
information upon which this information is based. You may want to read it and discuss it with your doctor.
Remember, no written summary can replace careful discussion with your doctor.

Manufactured By:
DABUR ONCOLOGY Plc.
Bordon, Hampshire GU35 0NF, UK

Distributed By:
HOSPIRA Worldwide, Inc.
Lake Forest, IL 60045, USA

EN-0869

Revised : August 2005

220002