CARBOPLATIN
WARNING
CARBOPLATIN (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 (carboplatin for injection) is supplied as a sterile, lyophilized
white powder available in single-dose vials containing 50 mg, 150 mg, and 450 mg
of carboplatin for administration by intravenous infusion. Each vial contains
equal parts by weight of 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).
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 5-7. It is virtually
insoluble in ethanol, acetone, and dimethylacetamide.
ACTIONS/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(squared) of 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 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 (300-500 mg/m(squared)).
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" section).
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/m(squared) 100 mg/m(squared)
Dose of carboplatin 300 mg/m(squared) 300 mg/m(squared)
Dose of Cytoxan 600 mg/m(squared) 600 mg/m(squared)
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% (49/83)
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)
MEDIAN NCIC SWOG
Carboplatin 59 weeks 49 weeks
Cisplatin 61 weeks 47 weeks
2-YEAR PFS(*)
Carboplatin 31% 21%
Cisplatin 31% 21%
95% C.I. of difference (-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 (carboplatin for injection)-
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
PERCENT(*) PERCENT(*) P-VALUES(**)
BONE MARROW
Thrombocytopenia, <100,000/mm(cubed) 70 29 <0.001
<50,000/mm(cubed) 41 6 <0.001
Neutropenia, <2,000 cells/mm(cubed) 97 96 n.s.
<1,000 cells/mm(cubed) 81 79 n.s.
Leukopenia, <4,000 cells/mm(cubed) 98 97 n.s.
<2,000 cells/mm(cubed) 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 CISPLATIN
ARM ARM
BONE MARROW PERCENT(*) PERCENT(*) P-VALUES(**)
Thrombocytopenia, <100,000/mm(cubed) 59 35 <0.001
<50,000/mm(cubed) 22 11 0.006
Neutropenia, <2,000 cells/mm(cubed) 95 97 n.s.
<1,000 cells/mm(cubed) 84 78 n.s.
Leukopenia, <4,000 cells/mm(cubed) 97 97 n.s.
<2,000 cells/mm(cubed) 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
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 (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:
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
(CYTOXAN(R)). 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 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 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, or mannitol.
CARBOPLATIN should not be employed in patients with severe bone marrow depression
or significant bleeding.
WARNINGS:
WARNING
CARBOPLATIN (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.
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.
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 (carboplatin for injection) 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.
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.
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.
PEDIATRIC USE:
Safety and effectiveness in pediatric patients have not been established.
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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
For a comparison of toxicities when carboplatin or cisplatin was given in
combination with cyclophosphamide, see the "COMPARATIVE TOXICITY" subsection of
the "CLINICAL STUDIES" section.
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER
FIRST LINE SECOND LINE
COMBINATION SINGLE AGENT
THERAPY(*) THERAPY(**)
PERCENT PERCENT
BONE MARROW
Thrombocytopenia, <100,000/mm(cubed) 66 62
<50,000/mm(cubed) 33 35
Neutropenia, <2,000 cells/mm(cubed) 96 67
<1,000 cells/mm(cubed) 82 21
Leukopenia, <4,000 cells/mm(cubed) 97 85
<2,000 cells/mm(cubed) 71 26
Anemia, <11 /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
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 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 (cubed) occurs in 25% of
the patients (35% of pretreated ovarian cancer patients); neutropenia with
granulocyte counts below 1,000/mm (cubed) occurs in 16% of the patients (21% of
pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm
(cubed) 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/mm
(cubed); 74% have neutrophil counts above 2,000/mm (cubed); 67% have leukocyte
counts above 4,000/mm (cubed).
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 (carboplatin for injection), 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 five 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. These reactions have been
successfully managed with standard epinephrine, corticosteroid, and
antihistamine therapy.
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.
OVERDOSAGE:
There is no known antidote for CARBOPLATIN 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, as a single agent, has been shown to be effective in patients with
recurrent ovarian carcinoma at a dosage of 360 mg/m(squared) 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 2,000 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/m(squared) I.V. on day 1 every 4 weeks for six cycles
(Alternatively see (FORMULA DOSING).
Cyclophosphamide (CYTOXAN(R))-600 mg/m(squared) I.V. on day 1 every 4 weeks for
six cycles. For directions regarding the use and administration of
cyclophosphamide (CYTOXAN(R)), 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 >2,000 125%
50-100,000 500-2,000 No Adjustment
<50,000 <500 75%
*Percentages apply to CARBOPLATIN (carboplatin for injection) 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
41-59 mL/min 250 mg/m(squared)
16-40 mL/min 200 mg/m(squared)
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.(REF.1,2)
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 (REF. 3-5) or renal function and desired platelet nadir.(REF. 6) Renal
excretion is the major route of elimination for carboplatin. (see
"ACTIONS/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
(REF. 3-5). In these studies, GFR was measured by 51Cr- EDTA, which has a good
correlation with creatinine clearance (REF. 7).
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/M(SQUARED).
The target AUC of 4-6 mg/mL.min using single agent CARBOPLATIN appears to provide
the most appropriate dose range in previously treated patients (REF. 4). This
study also showed a trend between the AUC of single agent CARBOPLATIN
administered to previously treated patients and the likelihood of developing
toxicity (REF.1.)
% Actual Toxicity in Previously Treated Patients
AUC Gr 3 or Gr 4 Gr 3 or Gr 4
(mg/mL.min) Thrombocytopenia Leukopenia
4 to 5 16% 13%
6 to 7 33% 34%
PREPARATION OF INTRAVENOUS SOLUTIONS
Immediately before use, the content of each vial must be reconstituted with
either Sterile Water for Injection, USP, 5% Dextrose in Water (D5W), or 0.9%
Sodium Chloride Injection, USP, according to the following schedule:
VITAL STRENGTH DILUENT VOLUME
50 mg 5 mL
150 mg 15 mL
450 mg 45 mL
These dilutions all produce a carboplatin concentration of 10 mg/mL.
CARBOPLATIN can be further diluted to concentrations as low as 0.5 mg/mL with 5%
Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.
STABILITY
Unopened vials of CARBOPLATIN for Injection are stable for the life indicated on
the package when stored at controlled room temperature 15 deg-30 deg C (59 deg-
86 deg F), and protected from light.
When prepared as directed, CARBOPLATIN solutions are stable for 8 hours at room
temperature (25 deg C). Since no antibacterial preservative is contained in the
formulation, it is recommended that CARBOPLATIN solutions be discarded 8 hours
after dilution.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration.
STORAGE
Store the unopened vials at controlled room temperature 15 deg-30 deg C (59 deg-
86 deg F). Protect unopened vials from light. 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.(REF. 8-14)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
REFERENCES:
1. Egorin MJ, et al: Pharmacokinetics and Dosage Reduction of cis- diammine(1,1-
cyclobutanedicarboxylato) Platinum in Patients with Impaired Renal Function.
Cancer Res 1984; 44:5432-5438.
2. Carboplatin, Etoposide, and Bleomycin for Treatment of Stage IIC Seminoma
Complicated by Acute Renal Failure. Cancer Treatment Reports, Vol. 71, No. 11,
pp. 1123-1124, November 1987.
3. Calvert AH, et al: Carboplatin dosage: Prospective evaluation of a simple
formula based on renal function. J Clin Oncol. 1989; 7:1748-1756.
4. Jodrell DI, et al: Relationships between carboplatin exposure and tumor
response and toxicity in patients with ovarian cancer. J Clin Oncol. 1992;
10:520-528.
5. Sorensen BT, et al: Dose-toxicity relationship of carboplatin in combination
with cyclophsphamide in ovarian cancer patients. Cancer Chemother Pharmacol.
1991; 28:397-401.
6. Egorin MJ, et al: Prospective validation of a pharmacologically based dosing
scheme for the cis-diamminedichloroplatinum (II) analogue
diamminecyclobutanedicarboxylatoplatinum. Cancer Res. 1985; 45:6502-6506.
7. Daugaard G, et al: Effects of cisplatin on different measures of glomerular
function in the human kidney with special emphasis on high-dose. Cancer
Chemother Pharmacol. 1988; 21:163-167.
8. 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.
9. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA
1985; 253(11):1590-1592.
10. National Study Commission on Cytotoxic Exposure-Recommendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study
Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
11. Clinical Oncological Society of Australia: Guidelines and Recommendations
for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428.
12. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983; (Sept/Oct)
258-263.
13. American Society of Hospital Pharmacists Technical Assistance Bulletin on
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
14. Controlling occupational exposure to hazardous drugs. (OSHA WORK PRACTICE
GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.
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