Product information
Name and pharmaceutical
form: CarbosinTM injection 10 mg/ml. Composition: CarbosinTM, injection 10 mg/ml containing 150 mg or 500 mg
carboplatin (cis-diammine (1.1-cyclobutanedicarboxylato)platinum) and 250 mg or 500 mg, respectively, of mannitol. Pharmacological properties: Carboplatin is a platinum coordination complex. After dissociation of the cyclobutanedicarboxylate moiety and subsequent aquation of the molecule it
interacts with DNA, producing predominantly interstrand cross-links. After intravenous administration of carboplatin plasma levels of intact drug
decline in a biphasic manner, with an initial half-life of 1-2 hours (t1/2 α) and a terminal half-life (t1/2
b) of 3-6 hours. Plasma levels are correlated
linearly with dose administered Unchanged carboplatin is virtually not bound to plasma proteins. However, irreversible protein binding of platinum
from carboplatin increases gradually to about 87% after 24 hours, and is slowly eliminated (t1/2 5 days). Plasma clearance of unchanged drug
occurs predominantly by renal excretion: about 70% of the total dose is excreted in 24 hours. In patients with impaired renal function (creatinine
clearance <60 ml/min) carboplatin excretion decreases with decreasing creatinine clearance; lower dosages of carboplatin should be used in this
patient group. Indications: Carboplatin is indicated for the palliative treatment of patients with advanced or recurrent ovarian carcinoma, including
patients previously treated with cisplatin. Furthermore, carboplatin may be used for the treatment of small cell lung carcinoma, and carcinoma of the
head and neck. Contra indications: Carboplatin is contraindicated in patients with a history of severe allergic reactions to platinum-containing
compounds, or mannitol (in powder for injection), In patients with severe myelosuppression, or in patients with severe renal function disturbances
(creatinine clearance < 20 ml/min.) Adverse effects; Bone marrow; Myelosuppression
i
s the major dose-limiting toxicity of carboplatin. Thrombocytopenia (platelets < 50,000/mm) is seen in most of the patients, with a nadir at about 3
weeks and full recovery at 4-5 weeks. Leukopenia (< 2,000/mm3
M3)
is usually less pronounced, with a nadir at about 3 weeks and a somewhat
slower recovery at 5 weeks. Anemia (hemoglobin < 2 mg/dl) is commonly seen, but usually not of a severe nature. Bone marrow depression is
more severe in patients with impaired renal function, patients with an inadequate bone marrow reserve, or patients with poor performance status.
Gastrointestinal: Nausea and vomiting are commonly seen, usually of mild to moderate degree, and in about 20% of patients severe. Nausea and
vomiting usually cease within 24 hours after treatment. ' Neurotoxicity: Peripheral neuropathies have been observed in 5% of the patients, mild
paresthesias occurring most frequently. The incidence and severity may be increased in patients previously treated with cisplatin. Clinical symptoms
of ototoxicity, mostly tinnitus, occur in 1 % of patients. Nephrotoxicity: Development of abnormal renal function tests is uncommon with carboplatin,
and preventive measures, such as hydration or forced diuresis are not necessary. Carboplatin treatment may result in a decrease in serum
electrolytes, including sodium, potassium, magnesium and calcium, but these electrolyte abnormalities are rarely associated with clinical
symptoms. Allergic reactions: Hype rsensitivity to carboplatin has been reported in 2% of the patients. These allergic reactions
h
ave been similar in nature and severity to those reported with other platinum-containing compounds, i.e., rash, urticaria, erythema and a pruritis.
Miscellaneous: Abnormal liver function tests have been reported, but are generally mild to moderate. Pain, asthenia, alopecia and mucositis are
rarely reported. Warnings and precautions: Bone marrow suppression (leukopenia, thrombocytopenia) is dose-dependent, and related to renal
function. Peripheral blo counts should be monitored frequently during and after treatment, and renal function should be assessed. Dose reductions
are generally necessary in patients with concomitant treatment with other myelosuppressive drugs, patients with inadequate bone marrow reserves
due to previous treatments or bone metastases, patients with impaired renal function (creatinine clearance < 60 ml/min), patients with poor
performance status and older patients. Carboplatin has limited nephrotoxic and ototoxic potential, but concomitant treatment with aminoglycosides
or other nephrotoxic or ototoxic agents may result in an increased risk for renal or auditory toxicity. Emesis during carboplatin treatment can be
effectively reduced by appropriate anti-emetic medication. Alternatively, emesis may be reduced by sustained administration schedules, e.g.,
dividing the total dose over 5 days or over a 24-hour i.v. infusion. The incidence of neurotoxicity may be increased in older patients, and patients
previously treated with cisplatin. 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, usually including adrenaline,
corticosteroids and antihistaminics. Use during pregnancy and lactation. Safe use of carboplatin during pregnancy or lactation has not been
established. Carboplatin has demonstrated embryotoxic and teratogenic effects in animals. Carboplatin has been shown to have a mutagenic
potential in vitro and in vivo. Therefore, the use of carboplatin should be * avoided if possible during pregnancy. It is not known whether carboplatin is
excreted in human milk. It is recommended that lactation is discontinued during carboplatin treatment. Interactions: Myelosuppression by carboplatin
may be more severe with prior or concomitant treatment with other myelosuppressive drugs. Concomitant treatment with other nephrotoxic or
ototoxic agents (e.g., aminoglycoside antibiotics) increases the risk of renal or auditory toxicity during carboplatin treatment. Dosage and method of administration:
CarbosinTM, injection 10 mg/ml and CarbosinTM , powder for injection are intended for intravenous use.
CarbosinTM , powder for injection
50 mg, 150 mg and 500 mg should be reconstituted with 5 ml, 15 ml or 50 ml, respectively, of water for injection, or glucose 5%. The recommended
starting
dose for previously untreated patients with normal kidney function is 400 mg/m2as a single i.v. dose, usually administered as a short term (15-60
min)
infusion, once every four weeks. Reduction of the initial dose to
300-320 mg/m2 is recommended with concomitant myelosuppressive therapy, or
other
risk factors (see Warnings and precautions). Patients with impaired renal function: Patients with a creatinine clearance < 60 ml/min are at increased
risk of severe myelopression. Recommended starting doses for these patients are: creatinine clearance 41-59 ml/min 250 mg/ml, and creatinine
clearance
20-40 ml/min 200 mg/m2. Insufficient date are available for patients with a creatinine clearance below 20 ml/min, and treatment is not recommended
in these cases. After the first course, dosage may be adjusted according to the patient's tolerance. Symptoms and treatment of overdosage: The
anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity. There is no known antidote for
carboplatin, lncompatibilities: Contact with aluminium containing injection or infusion material should be avoided. Dilution with sodium chloride
solution
(0.9%) may have a negative effect on the stability of carboplatin, and is therefore not recommended. Storage and shelf-life: The unopened vials
should
be stored at controlled room temperature 15' to 25'C. Protect from light. Since no antibacterial preservative is contained in the formulation, it is
recommended that carboplatin injection is discarded 8 hours after opening.
Packaging: CarbosinTM , injection 10 mg/ml containing 150 mg or 500 mg
carboplatin.
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General
Cisplatin, synthesised in
1845 (1), was
discovered
to be an agent with possible anti-tumour properties
in
1965 (2).
Since that time cisplatin has developed
into a versatile anti-tumour drug. Cisplatin binds to
DNA strands in the cell, thereby causing
irreparable damage leading to cell death. The
clinical break-through of cisplatin came with the
paper of Einhorn and Donohue in testicular cancer
(3). Since then, cisplatin appeared to be active in
many more cancers.
Therapeutic indications
Cisplatin is given alone, but usually in combination
with other cytostatic agents in the treatment of
testicular cancer, ovarian cancer, bladder cancer
and non-small cell lung cancer. it is also applied in
numerous other tumours, such as breast-, cervix-,
and head and neck cancer, osteosarcoma and
melanoma. Cisplatin is one of the most frequently
used cytostatics. Clinical research on cisplatin still
offers novel results.
Dosage
The dosage of cisplatin varies according to the
schedule applied, usually ranging from
50-100
Mg/M2 as a single intravenous administration, or
20
mg /M2 on each of
5
consecutive days. Some of
the frequently used schedules for the various
indications are depicted in the table.
Why Platosin
®
- Platosin is available in the most
widely used dosage forms to meet
the customer's needs
- Platosin is preservative free.
Pharmaceutical forms
Platosin ready to use solution
10, 25
and
50
mg
(0.5
mg/ml) Platosin ready to use solution
10, 25, 50
and
100 mg (1 mg/ml) |
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1. TRADE NAME OF THE MEDICINAL PRODUCT
Platosin® powder for injection.
Platosin®
0.05%,
injection.
Platosin® 0.1%, injection.
2.
QUALITATIVE AND QUANTITATIVE
COMPOSITION
Platosin® powder for injection contains
respectively 10 mg,
25
mg and
50
mg of cisplatin.
Platosin®
0.05%,
injection contains
0.5
mg/ml cisplatin.
Platosin®
0.1%, injection contains 1 mg/ml cisplatin.
3.
PHARMACEUTICAL FORM
Powder for injection.
Injection.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Platosin® is indicated for the
treatment of advanced and metastatic testis carcinoma,
advanced and metastatic ovarian carcinoma, and
advanced and metastatic bladder carcinoma.
4.2 Posology and method of administration
Platosin® powder
for injection 10 mg,
25
mg and
50
mg should be
reconstituted with 10 ml,
25
ml and
50
ml of water for
injections respectively. No aluminium containing infusion
or injection material should be used for administration of
Platosin® Before administration of cisplatin intravenous
hydration with at least 1 litre of
5%
glucose/0.9% saline
(1:1) is recommended. When urine flow is less than 100 ml
per hour,
100-200
ml
15%
mannitol may be administered.
Subsequently the
Platosin® solution should be added to
2
litres
5%
glucose/0.9% saline (1:1) and intravenously
administered in
6-8
hours; after administration an adequate
hydration and diuresis should be maintained during
24
hours. The next dose of
Platosin® should not be given until
the renal function has returned to normal.
The usual dose of
Platosin® is
50-100
mg/m2 as a single
intravenous administration or
20
mg/m2 intravenously on
each of
5
consecutive days. The dose may be adjusted,
depending on combination with other cytostatics. A
course can be administered once every
3-4
weeks,
depending on results of blood tests, renal function tests
and audiometric tests.
4.3
Contra-indications
Cisplatin should not be
administered to patients with a history of severe allergic
reactions to cisplatin or other platinumcontaining
compounds and patients with renal function impairment,
severe myelosuppression or hearing impairment.
4.4
Special warnings and special precautions for use
Existing renal insufficiency, disorders of hearing or bone
marrow suppression may worsen by administration of cisplatin. Patients should have a normal renal function
(creatinine clearance > 90 ml/min) prior to start of therapy
with
Platosin®
Before administration, adequate hydration
and diuresis should be ascertained. Appropriate antiemetic medication should be given, considering the
severity of nausea and vomiting. Audiometric monitoring
is recommended prior to and during therapy with cisplatin.
Cisplatin is mutagenic in bacteria and causes chromosomal
aberrations in animal cell cultures. Regarding the
mechanism of action carcinogenicity is possible, but not
proven. Anticonceptive therapy should be taken by both
men and women, during cisplatin treatment, as well as
during at least
3
months after treatment. After spillage of
cisplatin the contaminated skin should be washed
immediately with water and soap. Administration should
be stopped immediately in case of extravasation.
Subsequently
3-5
ml of blood should be obtained via the
infusion needle. A plastic surgeon might be consulted, a
corticosteroid injected in the effected area and a cold
compress should be used during
12
hours. Generally
cisplatin extravasation does not lead to serious problems.
4.5
Interaction with other medicaments and other forms of
interaction
Patients receiving cisplatin should not be
exposed to living vaccines. Partial or full protection can be
achieved with a killed vaccine. Concomitant use of drugs
with a potential ototoxic or nephrotoxic effect should be
avoided or accurately monitored. The combination of
cisplatin and aminoglycosides or cefalotine should be
avoided. Furosemide could also potentiate nephrotoxicity.
Pharmacodynamic interaction with vincaalkaloids could
lead to increased neurotoxicity. Interaction with radiation
during radiation therapy could also occur.
4.6
Pregnancy and lactation
Considering the
pharmacological effect toxicity after treatment during
pregnancy is possible. In animal experiments cisplatin was
proven harmful.
4.7
Effects on ability to drive and use machines
Because of
the frequent occurrence of nausea and vomiting
precaution is advised in undertaking actions which require
extra alertness, such as the use of machines and the
participation in traffic.
4.8
Undesirable effects
Kidneys: The most serious sideeffect of cisplatin is nephrotoxicity. This is the main doselimiting factor. Renal damage is doserelated and
cumulative; initially renal damage is reversible, but
repeated cisplatin administration may cause irreversible
renal function impairment. The risk of
nephrotoxicity can be reduced by prehydration and careful
monitoring. Nephrotoxicity is manifested by elevations in
BUN, serum uric acid and creatinine, and a decrease in
creatinine clearance.Electrolyte disturbances: Hypomagnesemia and
hypocalcemia are frequently reported.
Gastrointestinal tract: Marked nausea and vomiting occur
in almost all patients and usually start within a few hours
after start of therapy. Nausea and vomiting may persist for
1-7
days after treatment. The symptoms may be so severe
that discontinuation of therapy is indicated. Antiemetics
or spreading of drug administration over several hours
may cause less severe nausea and vomiting. Anorexia,
stomatitis and mucositis have been reported during
therapy of cisplatin. Increases of ASAT and ALAT are
observed, but these are mild and temporary.
Ototoxicity: Ototoxicity has been observed in about
30%
of patients treated with
50
mg/m2 of cisplatin, and is
manifested as tinnitus and hearing loss in the high
frequency range
(4000
8000 Hz); hearing loss of
frequencies in the speaking range occurs rarely. Hearing
loss may be unilateral and is dose dependent. Hearing
should be monitored carefully by audiometric tests.
Ototoxicity may be more severe in children or in the
elderly. Ototoxicity increases with cumulating dosage and
is irreversible.
Myelotoxicity: Myelosuppression occurs in
25-30%
of
patients receiving cisplatin, but is usually not severe. The
nadirs in platelet and leucocyte counts occur between day
18 and
23,
but normal values have returned by day
39.
At
higher doses of cisplatin leucocytopenia and
thrombocytopenia are more serious and may be
accompanied by anemia.
Neurotoxicity: Cisplatin causes a bilateral, sensoric
neuropathy, manifested by paresthesias, decreased
vibratory sensation, tactile sense and decreased deeptendon reflexes. Fits, amnesia, tremor, loss of taste and
orthostatic hypotension may occur. Optic neuritis, with
temporary blindness has been reported a few times.
Neurotoxicity is dose-dependent and may occur following
single dose administration, but especially after prolonged
treatment and it is often only slowly reversible.
Neurotoxicity may progress after discontinuation of
therapy.
Eye toxicity: Various grades of decrease of eye sight have
rarely been reported during combination therapy with
cisplatin.
Miscellaneous: Hyperuricemia may occur, especially in
patients receiving higher doses of cisplatin. Treatment
with allopurinol reduces uric acid plasma levels effectively.
Disorders in cardiac function have been reported.
Anaphylactoid reactions are rare and usually seen directly
after administration.
4.9
Overdose
Overdosage is associated with the usual
adverse effects of a more severe kind. Myclosuppression
should be treated with antibiotics and transfusions. Other
adverse effects are treated symptomatic.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Cisplatin is a platinum
coordination complex. After hydrolysis in the cell,
substituting one or two chloride ligands by water or
hydroxyl groups, the resulting molecule interacts with
DNA, RNA and proteins. Cross-linking of DNA is
probably the major mechanism of action.
5.2
Pharmacokinetic properties
Following intravenous
administration cisplatin is rapidly distributed to all tissues;
cisplatin does not penetrate the central nervous system to
any appreciable extent. The highest concentrations are
reached in liver, kidneys, bladder, muscle, skin, testes,
prostate, pancreas and spleen. Following intravenous
administration plasma elimination of filterable, free
cisplatin is biphasic with an initial and terminal half-life of
10-20
minutes and
32-53
minutes respectively. Elimination
of the total amount of cisplatin is triphasic with a half-life
of
14
minutes,
274
minutes and
53
days respectively.
90%
of cisplatin is bound to plasma proteins. Cisplatin is
eliminated primarily via the urine:
27-43%
of the
administered dose is excreted in the urine during the first
5
days after administration. Cisplatin is also excreted in bile.
5.3 Preclinical safety data
Considering the mechanism of action, the product is
mutagenic and in principle carcinogenic.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Powder for injection: mannitol,
sodiumchloride. Injection: sodium chloride, water for
injection.
6.2
Incompatibilities
Contact with aluminium containing
material should be avoided. Cisplatin decomposes in media
with low chloride content; the diluent used for
administration should contain a chloride concentration at
least equivalent to 0.45% sodium chloride.
6.3 Shelf life
If stored as indicated below, this medication can be used
until the date stated on the packaging. The shelf life is 3
years for all three products.
Platosin® contains no
preservative. It is recommended to use reconstituted
solutions within 8 hours. Reconstituted solutions and
injection 1 mg/ml should not be stored in the refrigerator,
because of risk of precipitation.
6.4 Special precautions for storage
Store at 15-25 C, protected from light.
6.5 Nature and contents of container
Brown glass vials for injection with butylrubber stopper.
Platosin powder for injection 10 mg, 25 mg and 50 mg. Platosin
0.05%, injection 0.5 mg/ml, 20 ml, 50 ml and 100 ml. Platosin
0.1%, injection 1 mg/ml, 10 ml, 50 ml and 100 ml.
7. MARKETING AUTHORIZATION HOLDER
Pharmachemie B.V. P.O. Box 552 2003 RN Haarlem The
Netherlands.
8. MARKETING AUTHORIZATION NUMBER
Registered in The Netherlands under RVG 09010, powder for
injection. RVG 09263, injection 0.05%. RVG 15255, injection
0.1%.
9. DATE OF (PARTIAL) REVISION OF THE TEXT
January 1996
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