Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1430
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PARAPLATIN (Injection, Powder, Lyophilized, For Solution)
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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 PARAPLATIN.<br/>Single-Agent Therapy: PARAPLATIN (carboplatin lyophilized powder) for INJECTION, as a
single agent, has been shown to be effective in patients with recurrent ovarian
carcinoma at a dosage of 360 mg/mIV on day 1
every 4 weeks (alternatively see Formula Dosing).
In general, however, single intermittent courses of PARAPLATIN should not
be repeated until the neutrophil count is at least 2,000 and the platelet
count is at least 100,000.<br/>Combination Therapy with Cyclophosphamide: In the chemotherapy of advanced ovarian cancer, an effective combination
for previously untreated patients consists of: PARAPLATIN���300 mg/mIV on day 1 every
4 weeks for 6 cycles (alternatively see Formula
Dosing). Cyclophosphamide���600 mg/mIV on day
1 every 4 weeks for 6 cycles. For directions regarding the use and administration
of cyclophosphamide please refer to its package insert. (See CLINICAL
STUDIES.) Intermittent courses of PARAPLATIN 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.<br/>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. PARAPLATIN is usually administered by an infusion lasting
15 minutes or longer. No pre- or post-treatment hydration or forced diuresis
is required.<br/>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 PARAPLATIN therapy, the incidence of severe leukopenia,
neutropenia, or thrombocytopenia has been about 25% when the dosage modifications
in the table below have been used. 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.<br/>Formula Dosing: Another approach for determining the initial dose of PARAPLATIN
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.) 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 PARAPLATIN target area under
the concentration versus time curve (AUC in mg/mL���min), has been proposed
by Calvert. In these studies, GFR was measured byCr-EDTA
clearance. The target AUC of 4 mg/mL���min to 6 mg/mL���min using single-agent
PARAPLATIN appears to provide the most appropriate dose range in previously
treated patients. This study also showed a trend between the AUC of single-agent
PARAPLATIN administered to previously treated patients and the likelihood
of developing toxicity.<br/>Geriatric Dosing: Because renal function is often decreased in elderly patients,
formula dosing of PARAPLATIN based on estimates of GFR should be used in elderly
patients to provide predictable plasma PARAPLATIN AUCs and thereby minimize
the risk of toxicity.<br/>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 (DW),
or 0.9% Sodium Chloride Injection, USP, according to the following schedule: These dilutions all produce a carboplatin concentration of 10 mg/mL. PARAPLATIN can be further diluted to concentrations as low as 0.5
mg/mL with 5% Dextrose in Water (DW) or 0.9% Sodium
Chloride Injection, USP.<br/>STABILITY: Unopened vials of PARAPLATIN are stable for the life indicated
on the package when stored at 25��C (77��F); excursions permitted from 15��-30��C
(59��-86��F) [see USP Controlled Room Temperature]. Protect from light. When prepared as directed, PARAPLATIN solutions are stable for
8 hours at room temperature (25��C). Since no antibacterial preservative is
contained in the formulation, it is recommended that PARAPLATIN solutions
be discarded 8 hours after dilution. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration.
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PARAPLATIN (carboplatin lyophilized
powder) 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-cyclobutanedicarboxylato(2-)-O,O���]-, (SP-4-2),
and has the following structural formula: Carboplatin is a crystalline powder with the molecular formula
of CHNOPt
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.
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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/mto 500 mg/mof
PARAPLATIN. 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 Cvalues 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- 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. PARAPLATIN dosages should, therefore, be reduced in these patients
. The primary determinant of PARAPLATIN clearance is glomerular
filtration rate (GFR) and this parameter of renal function is often decreased
in elderly patients. Dosing formulas incorporating estimates of GFR to provide predictable
PARAPLATIN plasma AUCs should be used in elderly patients to minimize the
risk of toxicity.
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PARAPLATIN is contraindicated in patients with a history of severe
allergic reactions to cisplatin or other platinum-containing compounds, or
mannitol. PARAPLATIN (carboplatin lyophilized powder) for INJECTION should
not be employed in patients with severe bone marrow depression or significant
bleeding.
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PARAPLATIN (carboplatin
lyophilized powder) for INJECTION NDC 0015-3213-30 50 mg vials, individually
cartoned. (Yellow flip-off seals)NDC 0015-3214-30 150 mg vials, individually cartoned. (Violet flip-off seals)NDC 0015-3215-30 450 mg vials,
individually cartoned. (Blue flip-off seals)<br/>Storage: Store the unopened vials at 25��C (77��F); excursions permitted from
15��-30��C (59��-86��F) [see USP Controlled Room Temperature]. Protect unopened
vials from light. Solutions for infusion should be discarded 8 hours after
preparation.<br/>Handling and Disposal: Procedures for proper handling and disposal of anti-cancer
drugs should be considered. Several guidelines on this subject have been published.There
is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate. To minimize the risk of dermal exposure, always wear impervious
gloves when handling vials containing PARAPLATIN lyophilized powder for injection.
This includes all handling activities in clinical settings, pharmacies, storerooms,
and home healthcare settings, including during unpacking and inspection, transport
within a facility, and dose preparation and administration.
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WARNING: PARAPLATIN (carboplatin lyophilized powder) 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 PARAPLATIN have been reported and
may occur within minutes of PARAPLATIN administration. Epinephrine, corticosteroids,
and antihistamines have been employed to alleviate symptoms.
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General: Needles or intravenous administration sets containing aluminum
parts that may come in contact with PARAPLATIN should not be used for the
preparation or administration of the drug. Aluminum can react with carboplatin
causing precipitate formation and loss of potency.<br/>Drug Interactions: The renal effects of nephrotoxic compounds may be potentiated by
PARAPLATIN.<br/>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.<br/>Pregnancy:<br/>Pregnancy Category D: See WARNINGS.<br/>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
PARAPLATIN treatment of the mother, it is recommended that breast feeding
be discontinued if the mother is treated with PARAPLATIN (carboplatin lyophilized
powder) for INJECTION.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established
(see WARNINGS;���audiologic
toxicity���).<br/>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 PARAPLATIN dosage .
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There is no known antidote for PARAPLATIN overdosage. The anticipated
complications of overdosage would be secondary to bone marrow suppression
and/or hepatic toxicity.
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CARBOPLATIN
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PARAPLATIN (Injection, Powder, Lyophilized, For Solution)
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For a comparison of toxicities when carboplatin
or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES: Comparative Toxicity. 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 PARAPLATIN as single-agent therapy.<br/>Hematologic Toxicity: Bone marrow suppression is the dose-limiting toxicity of PARAPLATIN.
Thrombocytopenia with platelet counts below 50,000/mmoccurs
in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia
with granulocyte counts below 1,000/mmoccurs
in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia
with WBC counts below 2,000/mmoccurs 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;
74% have neutrophil counts above 2,000/mm; 67%
have leukocyte counts above 4,000/mm. 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
PARAPLATIN, 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 PARAPLATIN.
Transfusions have been administered to 26% of the patients treated with PARAPLATIN
(44% of previously treated ovarian cancer patients). Bone marrow depression may be more severe when PARAPLATIN is combined
with other bone marrow suppressing drugs or with radiotherapy.<br/>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 PARAPLATIN, eitherby 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 PARAPLATIN 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%.<br/>Neurologic Toxicity: Peripheral neuropathies have been observed in 4% of the patients
receiving PARAPLATIN (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 PARAPLATIN. 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 PARAPLATIN is low, prolonged treatment, particularly in cisplatin
pretreated patients, may result in cumulative neurotoxicity.<br/>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 PARAPLATIN, 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 PARAPLATIN therapy.<br/>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 PARAPLATIN and autologous
bone marrow transplantation, severe abnormalities of liver function tests
were reported.<br/>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
PARAPLATIN, and these electrolyte abnormalities were rarely associated with
symptoms.<br/>Allergic Reactions: Hypersensitivity to PARAPLATIN 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, ie, rash, urticaria, erythema,
pruritus, and rarely bronchospasm and hypotension. Anaphylactic reactions
have been reported as part of postmarketing surveillance . These reactions have been successfully
managed with standard epinephrine, corticosteroid, and antihistamine therapy.<br/>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.<br/>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, hypertension, dehydration, and stomatitis have
been reported as part of postmarketing surveillance.
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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 PARAPLATIN treatment and, when
appropriate, until recovery is achieved. Median nadir occurs at day 21 in
patients receiving single-agent PARAPLATIN. In general, single intermittent
courses of PARAPLATIN should not be repeated until leukocyte, neutrophil,
and platelet counts have recovered. Since anemia is cumulative, transfusions may be needed during
treatment with PARAPLATIN, 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 PARAPLATIN
dosages in these patients should be appropriately reduced and blood counts should
be carefully monitored between courses. The use of PARAPLATIN in combination
with other bone marrow suppressing therapies must be carefully managed with
respect to dosage and timing in order to minimize additive effects. PARAPLATIN 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 PARAPLATIN was administered at higher than recommended doses in combination
with other ototoxic agents. PARAPLATIN 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 PARAPLATIN, lengthening
the duration of single intravenous administration to 24 hours or dividing
the total dose over 5 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 PARAPLATIN as secondary treatment. Loss of vision, which can be complete for light and colors, has
been reported after the use of PARAPLATIN 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 PARAPLATIN 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. High dosages of PARAPLATIN (more than 4 times the recommended
dose) have resulted in severe abnormalities of liver function tests. PARAPLATIN may cause fetal harm when administered to a pregnant
woman. PARAPLATIN 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.
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PARAPLATIN
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