CARBOPLATIN 10MG/ML CONCENTRATE FOR INFUSION

Active substance: CARBOPLATIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Carboplatin 10 mg/ml concentrate for solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of solution contains 10 mg of carboplatin.
One vial of 5/15/45 ml solution contains 50/150/450 mg of carboplatin.
For excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Carboplatin 10 mg/ml concentrate for solution for infusion is a clear,
colourless to faintly yellow solution, free from particles.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Carboplatin is indicated for the treatment of
1. Advanced ovarian carcinoma of epithelial origin in:
- first line therapy
- second line therapy, after other treatments have failed.
2. Small cell carcinoma of the lung, in association with other hemotherapeutic
agents.

4.2

Posology and method of administration
Dosage and administration
Route of administration: intravenous use.
Carboplatin should be used by the intravenous route only. The recommended
dosage of Carboplatin in previously untreated adult patients with normal
kidney function is 400 mg/m2 as a single i.v. dose administered by a short

term (15 to 60 minutes) infusion. Therapy should not be repeated until four
weeks after the previous Carboplatin course and/or until the neutrophil count
is at least 2,000 cells/mm3 and the platelet count is al least 100,000 cells/mm3.
Reduction of the initial dosage by 20-25% is recommended for those patients
who present with risk factors such as prior chemotherapy and/ or radiotherapy,
or low performance status (ECOG-Zubrod 2-4 or Karnofsky below 80).
Determination of the haematological nadir by weekly blood counts during the
initial courses of treatment with Carboplatin is recommended for future dosage
adjustment.
Impaired renal function
Patients with creatinine clearance values of less than 60 ml/min are at greater
risk to develop myelosuppression. The optimal use of Carboplatin in patients
presenting with impaired renal function requires adequate dosage adjustments
and frequent monitoring of both haematological nadirs and renal function.
In case of a glomerular filtration rate of ≤ 20 ml/min, carboplatin should not
be administered at all.
Dose recommendations by AUC:
As an alternative, the initial dose can be calculated using the Calvert formula, which
takes account of renal function (glomerular filtration rate [GFR]). This reduces the
risk of over- or underdosage caused by individual variations in renal function.

Calvert formula :
Dosage (mg) = (Target AUC*) × (GFR + 25)
Note : With the Calvert´s formula, the total carboplatin dose is calculated in
mg, not in mg/m2.
*Target AUC

Planned chemotherapy

Patient treatment status

5-7 mg/ml min

Monotherapy with carboplatin

Previously untreated

4-6 mg/ml min

Monotherapy with carboplatin

Previously treated

4-6 mg/ml min

Carboplatin plus cyclophosphamide

Previously untreated

Calvert´s formula should not be used in patients who have received extensive pretreatment with the following therapy regimens:

-Mitomycin C
-Nitrosourea
-combination therapy with doxorubicin/cyclophosphamide/cisplatin
-combination therapy with 5 or more agents
-radiation therapy ≥ 4500 rad, focused on 20 × 20 cm field or on more than
one field.
Therapy with carboplatin should be discontinued in the case of an
unresponsive tumour, progressive disease and/or occurrence of not tolerable
side effects.

Combination therapy
The optimal use of Carboplatin in combination with other myelosuppressive
agents requires dosage adjustments according to the regimen and schedule to
be adopted.
Paediatric patients:
There is insufficient information to support a dosage recommendation in the
paediatric population
Elderly (over 65 years old)
Dosage adjustment, initially or subsequently, may be necessary dependent on
the physical conditions of the patient.
Dilution
The product may be diluted with 5% Glucose for Injection to a concentration
as low as 0.5 mg/ml (500 micrograms/ml).
4.3.

Contraindications
Carboplatin is contra-indicated in patients with severe pre-existing renal
impairment (creatinine clearance at or below 20 ml/minute).
Carboplatin is contra-indicated in severely myelosuppressed patients.
Carboplatin is also contra-indicated in patients with hypersensitivity to
carboplatin or other platinum containing products, or to mannitol.
Carboplatin is contra-indicated in patients with bleeding tumours.
Carboplatin is contra-indicated during breast feeding.

4.4.

Special warnings and precautions for use
Carboplatin should be administered by individuals experienced in the use of
anti-neoplastic therapy.
Carboplatin myelosuppression is closely related to its renal clearance: patients
with abnormal kidney function or receiving concomitant therapy with other
drugs with nephrotoxic potential are likely to experience more severe and
prolonged myelotoxicity. Renal function parameters should, therefore, be
carefully assessed before and during therapy. Carboplatin courses should not
be repeated more frequently than monthly under normal circumstances.
Thombocytopenia, leucopenia and anaemia occur after administration of
Carboplatin. Frequent monitoring of peripheral blood counts is recommended
throughout and following therapy with Carboplatin. Carboplatin combination
therapy with other myelosuppressive compounds must be planned very
carefully with respect to dosages and timing in order to minimise additive

effects. Supportive transfusional therapy may be required in patients who
suffer severe myelosuppression.
Carboplatin can cause nausea and vomiting. Pre-medication with anti-emetics
has been reported to be useful in reducing the incidence and intensity of these
effects.
Renal function impairment may be encountered with Carboplatin. Although no
clinical evidence on compounding nephrotoxicity has been accumulated, it is
recommended not to combine Carboplatin with aminoglycosides or other
nephrotoxic compounds.
As for other platinum co-ordination compounds, allergic reactions to
Carboplatin have been reported. They may occur within minutes of
administration and should be managed with appropriate supportive therapy.
Anaphylactic-like reactions may also occur as with other platinum coordination compounds.
In patients pre-treated with platinum containing medicinal products, the risk of
allergic reactions, including anaphylaxis, is increased.
In old age, renal function may be impaired, and should be taken into account
for dosage, if necessary.
Neurotoxic effects, especially in patients older than 65 years and/or those
previously treated with cisplatin, have been reported.
A relationship between visual transient disturbances and too high dosages in
renally impaired patients has been reported.
Safety and effectiveness of carboplatin administration in children are not
proven.
The carcinogenic potential of Carboplatin has not been studied but compounds
with similar mechanisms of action and mutagenicity have been reported to be
carcinogenic.
Carboplatin can have genotoxic effects. Therefore, men being treated with
carboplatin are advised not to father a child during and up to 6 months after
treatment and to seek advice on conservation of sperm prior to treatment
because of the possibility of irreversible infertility due to therapy with
carboplatin.
Women should not become pregnant during treatment with carboplatin and
should use an effective method of contraception.
Peripheral blood counts, renal and liver function tests and serum electrolytes
should be monitored closely.
Precautions
Peripheral blood counts and renal function tests should be monitored closely.
Blood counts at the beginning of the therapy and weekly to assess

haematological nadir for subsequent dose adjustment are recommended.
Neurological evaluations should also be performed on a regular basis.

4.5.

Interactions with other medicinal products and other forms of interaction
Myelosuppression is worsened by therapy combining Carboplatin with other
compounds that are myelosuppressive. Carboplatin combination therapy with
other myelosuppressive compounds must be planned very carefully with
respect to dosage and timing in order to minimise additive effects.
Patients receiving concomitant therapy with other nephrotoxic potential are
likely to experience more severe and prolonged myelotoxicity. Although no
clinical evidence on compounding nephrotoxicity has been accumulate, it is
recommended not to combine Carboplatin with aminoglycosides or other
nephrotoxic compounds.
Administration of nephrotoxic and/or ototoxic medicinal products (e.g.
aminoglycosides, loop diuretics) during treatment with carboplatin may
increase organ toxicity.
The concurrent administration of carboplatin and chelating agents should be
avoided as it can theoretically lead to a decrease of the antineoplastic effect of
carboplatin. However, the antineoplastic effect of carboplatin was not
influenced by diethyl-dithiocarbamate in animal experiments or in clinical use.
A decrease in phenytoin serum levels has been observed in case of concurrent
administration of carboplatin and phenytoin. This may lead to reappearance of
seizures and may require an increase of phenytoin dosages.

4.6.

Pregnancy and lactation
Pregnancy
Carboplatin is suspected to cause serious birth defects when administered
during pregnancy. Carboplatin was shown to be embryotoxic and teratogenic
in rats. Carboplatin should not be used during pregnancy unless clearly
necessary. The mother should be informed about the risk to the fetus. Women
of child-bearing potential must use effective contraception during treatment.
See also section 4.4 “Special warnings and precautions for use”.
For women who are pregnant or become pregnant during therapy, genetic
counselling should be provided.
Lactation
It is unknown whether Carboplatin is excreted in human breastmilk. Due to
the risk of serious adverse effects of carboplatin, breastfeeding must be
discontinued during treatment with carboplatin.

4.7.

Effects on ability to drive and use machines
Carboplatin may cause nausea and vomiting, indirectly impairing the ability to
drive and use machines.

4.8.

Undesirable effects
Incidences of adverse reactions reported hereunder are based on cumulative
data obtained in a large group of patients with various pre-treatment
prognostic features.
The following frequencies have been used:

Very common (>1/10)

Common (>1/100, <1/10)

Uncommon (>1/1,000, <1/1000)

Rare (>1/10,000, <1/1,000)

Very rare (<1/10,000) including isolated reports
Neoplasms benign and malignant (including cysts and polyps)
Uncommon:
Secondary malignancies (including promyelocytic leukaemia which
occurred 6 years after monotherapy with carboplatin and preceding irradiation)
have been reported following administration of Carboplatin as a single agent
or in combination therapy (causal relationship not established).
Blood and lymphatic system disorders
Very common:
Myelosuppression, which is the dose-limiting toxicity of Carboplatin.
Myelosuppression may be more severe and prolonged in patients with
impaired renal function, extensive prior treatment, poor performance
status and age above 65. Myelosuppression is also worsened by therapy
combining Carboplatin with other compounds that are
myelosuppressive.
Myelosuppression is usually reversible and not cumulative when
Carboplatin is used as a single agent and at the recommended dosages
and frequencies of administration.
Thrombocytopenia. At maximum tolerated dosages of Carboplatin
administered as a single agent, thrombocytopenia, with nadir platelet
counts of less than 50 x 109/l, 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.
Leucopenia. This has occurred in approximately 20 % 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 haemoglobin decrease (≤ 9.5 mg/100 ml) has been observed in 48%
of patients. Anaemia occurs frequently and may be cumulative.
Common:

Haemorrhagic complications, usually minor, have also been reported.
Uncommon:
Infectious complications have occasionally been reported.
Rare:
Cases of febrile neutropenia have been reported.
Single cases of life-threatening infections and bleeding have occurred.
Immune system disorders
Common:
Allergic reactions to Carboplatin have been reported in less than 2% of
patients. These reactions are similar to those observed after
administration of other platinum-containing compounds, i.e. skin rash,
urticaria, erythema, fever with no other apparent cause and pruritus.
Rare:
Cases of bronchospasm, hypotension, and anaphylactic shock requiring
adequate treatment (epinephrine, antihistamines, corticosteroids) may
occur.
Metabolism and nutrition disorders
Very common:
Decrease in serum electrolytes (magnesium, potassium, sodium and,
rarely, calcium) have been reported after treatment with Carboplatin
but have not been reported to be severe enough to cause the appearance
of clinical signs or symptoms.
Rare:
Isolated cases of hyponatremia have been reported, but a causal
connection is not proven.
Nervous system disorders
Common:
The incidence of peripheral neuropathies after treatment with
Carboplatin is 6%. In the majority of the patients neurotoxicity is
limited to paraesthesia and decreased deep tendon reflexes. The
frequency and intensity of this side effect increases in patients above
the age of 65 years or patients previously treated with cisplatin.
Paraesthesia present before commencing Carboplatin therapy,
particularly if related to prior cisplatin treatment, may persist or worsen
during treatment with Carboplatin.
Central nervous symptoms have occasionally been reported, however,
they seem to be frequently attributed to concomitant antiemetic
therapy.
Eye disorders
Rare:
Transient visual disturbances, sometimes including transient sight loss,
have been reported rarely with platinum therapy. This is usually
associated with high dose therapy in renally impaired patients.
Ear and labyrinth disorders
Very common:

-

Subclinical decrease in hearing acuity, consisting of high-frequency
(4000- 8000 Hz) hearing loss determined by audiogram, has been
reported in 15 % of the patients treated with Carboplatin.
Common:
Only 1 % of patients present with clinical symptoms, manifested in the
majority of cases by tinnitus. In patients who have been previously
treated with cisplatin and have developed hearing loss related to such
treatment, the hearing impairment may persist or worsen. Clinically
significant hearing loss has occurred in children who received
Carboplatin dosages higher than recommended and combined with
other ototoxic drugs.
Cardiovascular disorders
Cardiovascular events (cardiac failure, embolism) as well as
cerebrovascular events (apoplexy) have been reported in single cases
(causal relationship with Carboplatin not established). Single cases of
hypertension have been reported.
Gastrointestinal disorders
Very common:
Nausea and/or vomiting. Nausea without vomiting occurs in about a
quarter of the patients receiving Carboplatin; vomiting has been
reported in half of the patients and one-third of these suffer severe
emesis. Nausea and vomiting usually disappear within 24 hours after
treatment and are usually responsive to (and may be prevented by) antiemetic medication. Vomiting that could not be controlled by drugs was
observed in only 1% of patients. A quarter of patients experiences no
nausea or vomiting. Vomiting seems to occur more frequently in
previously treated patients, particularly in patients pre-treated with
cisplatin.
Painful gastro-intestinal disorders. These have occurred in 17 % of
patients.
Common:
Diarrhoea and constipation have occurred in 6 % and 4 % of patients,
respectively.
Mucositis
Rare:
Taste alteration
Isolated cases of anorexia have been reported.
Hepato-biliary disorders
Very common:
Abnormalities of liver function tests (usually mild to moderate). These
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.
Rare:

-

Severe hepatic dysfunction (including acute liver necrosis) has been
reported after administration of higher than recommended Carboplatin
dosages.

Skin and subcutaneous disorders
Common:
Alopecia
Renal and urinary disorders
Very common:
Elevation of blood urea or serum creatinine levels. Renal toxicity is
usually not dose-limiting in patients receiving Carboplatin, nor does it
require preventive measures such as a high volume fluid hydration or
forced diuresis. Nevertheless increasing blood urea or serum creatinine
levels can occur commonly.
Common:
Renal function impairment, as defined by a 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. It is not clear whether an
appropriate hydration programme might overcome such an effect, but
dosage reduction or discontinuation of therapy is required in the
presence of moderate alteration of renal function (creatinine clearance
41 to 59 ml/ min) or severe alteration (21 - 40 ml/ min). Carboplatin is
contra-indicated in patients with a glomerular filtration rate at or below
20 ml/ min.
General disorders and administration site conditions
Very common:
Hyperuricaemia, which is observed in about one quarter of patients.
Serum levels of uric acid can be decreased by allopurinol.
Asthenia
Common:
Malaise
Uncommon:
Injection site reactions, such as pain, erythema, swelling, urticaria and
necrosis, have been reported.
Fever and chills without evidence of infection have occurred.
Rare:
Haemolytic uraemic syndrome occurred in single cases.

4.9.

Overdose
Since no known antidote exists for Carboplatin, every possible measure should
be undertaken to avoid an overdose.
Symptoms of intoxication
Carboplatin was administered in Phase I studies at a dosage of up to 1600

mg/m2 i.v. per course. At this dosage, life-threatening haematological side
effects with granulocytopenia, thrombocytopenia and anaemia were observed.
The granulocyte, thrombocyte and haemoglobin nadir were observed between
days 9-25 (median: days 12-17). The granulocytes had reached values of ≥
500/μl after 8-14 days (median: 11) and the thrombocytes values of ≥
25.000/μl after 3-8 days (median: 7).
The following non-haematological side effects also occurred: renal function
disturbances with a 50% drop in the glomerular filtration rate, neuropathy,
ototoxicity, sight loss, hyperbilirubinaemia, mucositis, diarrhoea, nausea and
vomiting with headache, erythema, and severe infection. In the majority of
cases, hearing disturbances were transient and reversible.
Therapy of intoxication
There is no specific antidote. Symptomatic measures should be taken to
sustain the patient through any period of toxicity that might occur. Bone
marrow transplantation and transfusions (thrombocytes, blood) can be
effective measures of managing haematological side effects.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, platinum compounds.
ATC code: L01XA02.
Carboplatin has biochemical properties similar to that of cisplatin, thus
producing predominantly interstrand and intrastrand DNA crosslinks.
Paediatric patients:
Safety and efficacy in children have not been established.

5.2

Pharmacokinetic properties
Following administration of Carboplatin in man, linear relationship exists
between dose and plasma concentrations of total and free ultra-filterable
platinum. The area under the plasma concentration versus time curve for total
platinum also shows a linear relationship with the dose.
Repeated dosing during four consecutive days did not produce an
accumulation of platinum in plasma. Following the administration of
Carboplatin reported values for the terminal elimination half-lives of free
ultrafilterable platinum and Carboplatin in man are approximately 6 hours and
1.5 hours respectively. During the initial phase, most of the free ultra-filterable
platinum is present as Carboplatin. The terminal half-life for total plasma

platinum is 24 hours. Approximately 87% of 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. Total body
and renal clearance of free ultra-filterable platinum correlate with the rate of
glomerular filtration but not tubular secretion.
Carboplatin clearance has been reported to vary by 3- to 4- fold in paediatric
patients. As for adult patients, literature data suggest that renal function may
contribute to the variation in carboplatin clearance.
5.3.

Preclinical safety data
In animals, symptoms of acute toxicity consisted of emesis, anorexia, adipsia,
postural changes, troubled respiration and diarrhoea. Symptoms of long term
toxicity included myelosuppression, depression of the immune system,
necrosis of the mucosae of the gastrointestinal system, reduction in body
weight , increases in the levels of enzymes of the liver and blood urea
nitrogen, bleeding, bacterial infection, bronchitis, damage to the retinae, mild
ototoxicity and damage to the kidneys. Carboplatin induces cytogenetic effects
suggesting that it is likely to be mutagenic/carcinogenic. Reproduction and
teratology: increases in toxicity to the mother and foetus were observed in a
dose dependent fashion. Changes to the foetuses included alterations to the
weight and length of the body, increases in the incidences and severity of
abnormalities to the skeleton and internal organs. At doses higher than
4mg/kg/day, spontaneous abortion of most of the foetuses and severe
deformities to the skeletons of surviving foetuses were observed.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Mannitol, Water for Injection.

6.2.

Incompatibilities
This medicinal product should not be mixed with other medical products
except those mentioned under 4.2. “Dilution”.
This product should not be used with aluminium-containing infusion
assemblies, syringes and injection needles. The antineoplastic activity can be
reduced.

6.3.

Shelf Life

18 months
After first opening/dilution
Immediate and single use.
Chemical and physical in-use stability has been demonstrated for three hours
at room temperature (15-25°C) and for 24 hours at 2-8°C. From a
microbiological point of view, the product should be used immediately. If not
used immediately, in use storage times and conditions are the responsibility of
the user and would normally not be longer than 24 hours at 2 to 8°C, unless
reconstitution / dilution has taken place in controlled and validated aseptic
conditions.
6.4.

Special precautions for storage
Do not store above 25 °C.
Keep container in the outer carton in order to protect from light.
Storage conditions after first opening/dilution
Do not store above 25 °C.
Protect from light.

6.5

Nature and contents of container
Amber coloured glass vials, USP type I with chlorobutyl, black teflon-coated,
grey stoppers with an aluminium seal covered with a polypropylene snap-cap.
Pack sizes:
Box of 1 vial of 5 ml, 15 ml and 45 ml
Boxes of 5 and 10 vials of 5 ml, 15 ml and 45 ml (each packed separately in a
box, wrapped together with transparent shrink foil).
Not all pack sizes may be marketed

6.6

Special precautions for disposal
Dilution: The product may be diluted with 5% Glucose for Injection to
concentrations as low as 0.5 mg/ml (500 micrograms/ml).
When diluted as directed, Carboplatin is chemically and physically stable for
three hours at room temperature (15-25°C) and for 24 hours at 2-8°C.
The solution is to be inspected visually for particulate matter and discoloration
prior to administration. The solution should only be used if the solution is clear
and free from particles.

For single use only. Any unused solution should be discarded.
Guidelines for safe handling of anti-neoplastic agents:
1 Trained personnel should handle the drug
2 This should be performed in a designated area
3 Adequate protective gloves should be worn.
4 Precautions should be taken to avoid the drug accidentally coming into
contact with the eyes. In the event of contact with the eyes, wash with water
and/or saline.
5 The cytotoxic preparation should not be handled by pregnant staff.
6 Adequate care and precautions should be taken in the disposal of items
(syringes, needles etc) used to reconstitute cytotoxic drugs. Excess material
and body waste may be disposed of by placing in double sealed polythene
bags and incinerating at a temperature of 1000°C. Liquid waste may be
flushed with copious amounts of water.
Dilution:
7 The work surface should be covered with disposable plastic-backed
absorbent paper.
8 Use Luer-Lock fittings on all syringes and sets. Large bore needles are
recommended to minimise pressure and the possible formation of aerosols.
The latter may also be reduced by the use of a venting needle.

7.

MARKETING AUTHORISATION HOLDER
Pharmachemie B.V.
Swensweg 5
PO Box 562
2003 RN Haarlem
The Netherlands

8.

MARKETING AUTHORISATION NUMBER
PL 04946/0028

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17 March 2004

10

DATE OF REVISION OF THE TEXT
05/06/2009

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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