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Physician's Package Insert
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‫קרבופלטין‬
CARBOPLATIN
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SOLUTION FOR INJECTION
‫להזרקה לתוך הוריד‬
Composition
Each ml contains:
Active Ingredient
Carboplatin
10 mg
Other Ingredients
Mannitol, water for injection.
Mechanism of Action
Carboplatin is a synthetic analogue of cisplatin. Like cisplatin, carboplatin
interferes with DNA intrastrand and interstrand crosslinks in cells exposed to the
drug. DNA reactivity has been correlated with cytotoxicity.
Pharmacokinetics
Following administration of carboplatin in man, linear relationships exist between
dose and plasma concentrations of total and free ultrafilterable platinum.
Repeated dosing during 4 consecutive days did not produce an accumulation of
platinum in plasma.
Following administration of carboplatin, reported values for the terminal elimination
half-lives of free ultrafilterable platinum and carboplatin in man were approximately 6
hours and 1.5 hours, respectively. During the initial phase, most of the free
ultrafilterable platinum is present as carboplatin. The terminal half-life for total plasma
platinum is 24 hours. Approximately 87% of the plasma platinum is protein-bound
within 24 hours following administration.
Carboplatin is excreted primarily in the urine with recovery of approximately 70% of
the administered platinum within 24 hours. Most of the drug is excreted in the first
6 hours. Excretion of carboplatin is by glomerular filtration.
Patients with poor renal function have a higher area under curve (AUC) for total
platinum, and a reduction in dosage is recommended.
Indications
Advanced ovarian carcinoma:
Initial Treatment: Carboplatin is indicated for the treatment of advanced ovarian
carcinoma in established combination with other approved chemotherapeutic
agents.
Secondary Treatment: Carboplatin is indicated for the palliative treatment of
patients with advanced ovarian carcinoma recurrent after prior chemotherapy,
including patients who have been previously treated with cisplatin.
Metastatic small cell carcinoma of the lung.
Contraindications
History of severe allergic reactions to cisplatin or other platinum-containing
compounds.
Severe bone marrow suppression or significant bleeding.
Severe pre-existing renal impairment (creatinine clearance at or below
20 ml/minute).
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Warnings
General
Carboplatin should only be administered under the supervision of a physician
experienced in the use of cancer chemotherapeutic agents. Adequate diagnostic and
treatment facilities must be readily available to ensure appropriate management of
therapy, and treatment of possible complications.
Anaphylaxis
As with other platinum co-ordination compounds, allergic reactions, including
anaphylactic-like reactions to carboplatin, have been reported. These may occur
within minutes of administration and should be managed with appropriate supportive
therapy. Epinephrine, corticosteroids, and antihistamines have been employed to
alleviate symptoms.
Myelosuppression
Bone marrow suppression (leukopenia, neutropenia and thrombocytopenia) is
dose-dependent and may be severe, and is also the dose-limiting toxicity. Peripheral
blood counts (including platelets, white blood cells, neutrophils, and hemoglobin)
should be frequently monitored during carboplatin treatment and, when appropriate,
until recovery is achieved.
In general, single intermittent courses of carboplatin should not be repeated until
leukocyte, neutrophil and platelet counts have recovered.
Myelosuppression, as a result of carboplatin treatment, is closely related to the
renal clearance of the drug. Therefore, in patients who have abnormal renal function
or who are receiving concomitant therapy with nephrotoxic drugs, myelosuppression
especially thrombocytopenia, may be more severe and prolonged. Renal function
parameters should therefore be assessed prior to, during, and after therapy.
Anemia has been observed during treatment with carboplatin; since it is
cumulative, transfusions may be needed particularly in patients receiving prolonged
therapy.
The occurrence, severity and protraction of toxicity is likely to be greater in patients
who have received extensive prior treatment for their disease, have poor
performance status, and who are more than 65 years of age.
Effect on Reproduction and Fertility
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in
patients receiving antineoplastic therapy, especially alkylating agents.
In general, these effects appear to be related to dose and length of therapy and may
be irreversible. Prediction of the degree of testicular or ovarian function impairment is
complicated by the common use of combinations of several antineoplastics, which
makes it difficult to assess the effects of individual agents.
Mutagenicity
Carboplatin has been shown to be mutagenic both in vitro and in vivo.
Carcinogenicity
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.
Teratogenicity
Carboplatin has been shown to be embryotoxic and teratogenic in rats receiving
the drug during organogenesis.
Use in Pregnancy
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Adequate and well-controlled studies in pregnant women have not been reported;
however, carboplatin has been shown to be embryotoxic and teratogenic in rats. In
the event the drug has been used in a pregnant patient, or if the patient becomes
pregnant while on treatment with carboplatin she should be apprised of the potential
hazard to the fetus. Women of childbearing potential should be advised to avoid
becoming pregnant.
Use in Lactation
It is not known whether carboplatin is excreted in breast milk. To avoid possible
harmful effects in the infant, breastfeeding is not advised during carboplatin therapy.
Use in the Elderly
Incidence of peripheral neurotoxicity is increased and myelotoxicity may be more
severe in patients over 65 years of age. In addition, elderly patients are more likely to
have age-related renal function impairment, which may require dosage reduction and
careful monitoring of blood counts in patients receiving carboplatin.
Adverse Reactions
Hematologic
Myelosuppression is the dose-limiting toxicity of carboplatin. It is usually reversible
and is not cumulative when carboplatin is used as a single agent and at the
recommended dosage regimens.
Thrombocytopenia, with nadir platelet counts occurs in about a third of the patients.
The nadir usually occurs between days 14 and 21, with recovery within 35 days from
the start of therapy. Leukopenia has also occurred in approximately a fifth of patients
but its recovery from the day of nadir (day 14-28) may be slower and usually occurs
within 42 days from the start of therapy. A hemoglobin decrease may also be
observed.
The hematologic effects, although usually reversible, have resulted in infectious or
hemorrhagic complications in patients treated with carboplatin, with drug-related
death occurring rarely.
Gastrointestinal
Although carboplatin is significantly less emetogenic than cisplatin, vomiting (65%
of the patients, and in about 33% of these patients it is severe) and nausea without
vomiting (quarter of the patients) were reported.
Nausea and vomiting usually occur 6 to 12 hours after administration of carboplatin
and disappear within 24 hours. They are readily controlled (or may be prevented) by
antiemetic medication. Emesis was increased when carboplatin was used in
combination with other emetogenic compounds.
Other gastrointestinal effects observed frequently were pain, diarrhea and
constipation.
Renal
Renal toxicity is usually not dose-limiting in patients receiving carboplatin, nor does
it require preventive measures such as high volume fluid hydration or forced diuresis.
Nevertheless, increasing blood urea or serum creatinine levels can occur. Renal
function impairment, as defined by decrease in the creatinine clearance below
60 ml/min, may also be observed. The incidence and severity of nephrotoxicity may
increase in patients who have impaired kidney function before carboplatin treatment.
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.
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Decreases in serum magnesium, potassium and calcium have occurred after
treatment with carboplatin but have not been reported to be severe enough to cause
the appearance of clinical signs or symptoms.
Neurologic
In the majority of patients, neurotoxicity is limited to paresthesias and decreased
deep tendon reflexes. Peripheral neuropathies have been observed infrequently,
however its incidence is increased in patients older than 65 years and in patients
previously treated with cisplatin. Paresthesias present before commencing therapy
with carboplatin, particularly if related to prior cisplatin treatment, may persist or
worsen during treatment with carboplatin.
Special senses
Transient visual disturbances, sometimes including transient sight loss, have been
reported rarely with carboplatin therapy. This is usually associated with high dose
therapy in renally-impaired patients.
Ototoxicity, usually manifested as tinnitus, has been reported. In patients who
developed hearing loss as a result of cisplatin therapy, the impairment may persist or
worsen.
Dysgeusia has been rarely reported.
Other
Abnormalities of liver function tests (usually mild to moderate) have been reported
with carboplatin in about one-third of the patients with normal baseline values. The
alkaline phosphatase level is increased more frequently than SGOT, SGPT or total
bilirubin. The majority of these abnormalities regress spontaneously during the
course of treatment.
Hypersensitivity reactions, similar to those seen after cisplatin treatment, have
been observed. They included: erythematous rash, fever, pruritus, bronchospasm
and hypotension. These reactions have been successfully managed with standard
epinephrine, corticosteroid and antihistamine therapy.
Pain, asthenia, alopecia, cardiovascular, respiratory, genitourinary and mucosal
side effects, were also reported.
Precautions
Peripheral blood counts and renal function should be monitored closely. Blood
counts should be performed prior to commencement of carboplatin therapy and
weekly to assess hematologic nadir, for subsequent dose adjustments. Lowest levels
in white cells and platelets are seen between days 14 and 28, and days 14 and 21
respectively, after initial therapy. A greater reduction in platelets is seen in patients
who have received extensive myelosuppressive chemotherapy than in untreated
patients. White blood cell counts less than 2,000 cells/mm3 or platelets less than
50,000 cells/mm3 may necessitate postponement of carboplatin therapy until bone
marrow recovery is evident, usually within 5 to 6 weeks.
Renal toxicity is not usually dose-limiting. Pretreatment and post-treatment
hydration is not necessary. However, about a quarter of patients show decreases in
creatinine clearance below 60 ml/min. and, less frequently, rises in serum creatinine
and blood urea nitrogen may be seen in patients who have previously experienced
nephrotoxicity as a result of cisplatin therapy.
Drug Interactions
Carboplatin/Bone Marrow Suppressants: Concurrent use of carboplatin with other
myelosuppressive therapies may necessitate changes in the dosage or frequency of
carboplatin administration in order to minimize additive myelosuppressive effects.
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Carboplatin/Cisplatin: Incidence of carboplatin-induced neurotoxicity or ototoxicity is
increased in patients previously treated with cisplatin; use of carboplatin worsens
pre-existing cisplatin-induced neurotoxicity or ototoxicity.
Carboplatin/Nephrotoxic drugs: Carboplatin has limited nephrotoxic potential, but
concomitant treatment with nephrotoxic compounds may increase or exacerbate
toxicity due to carboplatin induced changes in renal clearance.
Carboplatin/Vaccines, killed virus: Because normal defense mechanisms may be
suppressed by carboplatin therapy, the patient’s antibody response to the vaccine
may be decreased. The interval between discontinuation of medications that cause
immunosuppression and restoration of the patient’s ability to respond to the vaccine
depends on the intensity and type of immunosuppression-causing medication used,
the underlying disease, and other factors; estimates vary from 3 months to 1 year.
Carboplatin/Vaccines, live virus: Because normal defense mechanisms may be
suppressed by carboplatin therapy, concurrent use with a live virus vaccine may
potentiate the replication of the vaccine virus, may increase the adverse effects of the
vaccine virus, and/or may decrease the patient’s antibody response to the vaccine;
immunization of these patients should be undertaken only with extreme caution after
careful review of the patient’s hematologic status and only with the knowledge and
consent of the physician managing the carboplatin therapy. The interval between
discontinuation of medications that cause immunosuppression and restoration of the
patient’s ability to respond to the vaccine depends on the intensity and type of
immunosuppression-causing medication used, the underlying disease, and other
factors; estimates vary from 3 months to 1 year.
Patients with leukemia in remission should not receive live virus vaccine until at
least 3 months after their last chemotherapy. In addition, immunization with oral
polio-virus vaccine should be postponed in persons in close contact with the patient,
especially family members.
Dosage and Administration
Notes:
Carboplatin Injection does not contain any antimicrobial preservative; it is intended
for single-dose administration only.
Any carboplatin solution remaining 8 hours at room temperature after dilution or
constitution, must be discarded.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Administration
This preparation is intended for intravenous use only, usually by an infusion lasting
15 minutes or longer. It may be given to outpatients since hydration is not required.
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.
Dosage
Advanced ovarian carcinoma:
Initial Treatment
In patients with advanced ovarian carcinoma, carboplatin administered in
combination therapy as established by specialists, is recommended at a dosage of
300 mg/m2 I.V. on day 1 every 4 weeks for six cycles.
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Secondary Treatment
Carboplatin, as monotherapy, has been shown to be effective in patients with
recurrent ovarian carcinoma. The recommended dosage is 360 mg/m2 I.V. on day 1
every 4 weeks.
Metastatic Small Cell Carcinoma of the Lung
The recommended dosage is 400 mg/m2 as a single I.V. dose administered by a
short-term (15 - 60 minutes) infusion. Therapy should not be repeated until 4 weeks
after the previous carboplatin course.
The optimal use in combination with other myelosuppressive agents requires
dosage adjustments according to the regimen and schedule to be adopted.
Dosage Adjustment
Reduction of the initial dosage by 20-25 % is recommended for those patients who
present with risk factors such as prior myelosuppressive treatment and low
performance status (ECOG-Zubrod 2-4 or Karnofsky below 80).
Determination of the hematological nadir by weekly blood counts during the initial
courses of treatment with carboplatin is recommended for future dosage adjustment.
Patients with Renal Function Impairment
Patients with creatinine clearance values below 60 ml/min. are at increased risk of
severe bone marrow suppression. In renally-impaired patients who received singleagent 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 Dose
Clearance
on Day 1
41-59 ml/min
250 mg/m2
16-40 ml/min
200 mg/m2
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.
In general, intermittent courses of carboplatin should not be repeated until the
neutrophil count is at least 2,000 cells/mm3 and platelet count is at least 100,000
cells/mm3.
Dilution of Carboplatin Injection
Carboplatin Injection may be diluted to the required strength with Water for
Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, to
concentrations as low as 0.5 mg/ml.
Overdosage
Since no known antidote exists for carboplatin, every possible measure should be
undertaken to avoid an overdose.
The following are general guidelines in the avoidance of overdosage of anticancer
agents:
#
Chemotherapy should only be administered under the supervision of a physician
experienced in the use of cancer chemotherapeutic agents.
#
Adequate diagnostic and treatment facilities must be readily available to ensure
appropriate management and treatment of possible complications.
#
All personnel involved in handling chemotherapeutic agents should be fully
knowledgeable of the potential dangers. Administration of these drugs should
never be considered a routine task.
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#
#
Charts of normal doses of chemotherapeutic agents should be available in all
nursing stations and wherever drugs are prepared or administered.
Dosage should be carefully calculated as mg/kg or mg/m2, as applicable, and
recorded in a chart. The chart should include the total dose expressed as
concentration in the total volume to be administered.
Manifestations
The anticipated complications of overdosage would be secondary to bone marrow
suppression and/or hepatic toxicity.
Treatment
There is no known antidote for carboplatin. Symptomatic measures should be
taken to sustain the patient through any period of toxicity that might occur.
Handling and Disposal
As with all cytotoxic preparations, the following special precautions should be
taken for safe handling and disposal:
# Trained personnel only should prepare the drug. Pregnant staff should not be
involved in its handling.
# Preparation of the drug should be performed in a designated area, ideally in a
vertical laminar flow hood (Biological Safety Cabinet - Class II). The work surface
should be covered with disposable plastic-backed absorbent paper.
# Adequate protective clothing should be worn, i.e. PVC gloves, safety glasses,
disposable gowns and masks. In the event of contact with the eyes, wash with
copious amounts of water or saline.
# Luer-Lock fittings should be used on all syringes and sets. The possible formation
of aerosols may be reduced by using large-bore needles and venting needles.
# All unused material, needles, syringes, vials and other items which have come into
contact with cytotoxic drugs should be segregated, placed in double-sealed
polyethylene bags and incinerated at 1000º C or more. Excreta should be similarly
treated. Liquid waste should be flushed away with copious amounts of water.
Storage
The unopened vial should be stored in a dark place at room temperature.
Any carboplatin solution remaining 8 hours after dilution or constitution, must be
discarded.
Drug Registration No: 42052554005
Presentation
Carboplatin Injection 10 mg/ml in the following sizes: vials of 5 cc, 15cc and
45 cc.
Manufacturer
Pharmachemie BV,
Haarlem, Holland
For
Abic Ltd.
Teva Group
Importer
Salomon Levin & Elstein Ltd
P.O.Box 3696, Petach Tikva, 49133
Carboplatin inj, 30.3.2003, RH