INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo P&U CISPLATIN CSV
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

P&U CISPLATIN CSV

P&U CISPLATIN CSV 10 mg/10 mL INJECTION
P&U CISPLATIN CSV 50 mg/50 mL INJECTION
P&U CISPLATIN CSV 100 mg/100 mL INJECTION

COMPOSITION:
Each 1 mL contains 1,0 mg cisplatin.

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents

PHARMACOLOGICAL ACTION:
CISPLATIN is a platinum co-ordination compound with antitumour properties. The platinum complexes can react with DNA forming both interstrand and intrastrand DNA cross links.
In addition to its reactivity with DNA, CISPLATIN can react with other nucleophiles, such as sulfhydryl groups of proteins.
There is no phase specificity in the action of CISPLATIN on the cell cycle. With rapid intravenous administration the medicine has an initial half-life in plasma of 25 - 50 minutes; concentrations decline subsequently with a half-life of 58 - 73 hours. More than 90 % of the platinum in the blood is bound to plasma proteins. High concentrations of CISPLATIN are found in the kidney, liver, intestine and testes, but there is poor penetration into the central nervous system.

INDICATIONS:
CISPLATIN is indicated for advanced, non-seminomatous testicular cancer in combination therapy with bleomycin and vinblastine.
Carcinoma of the ovary, particularly when used with cyclophosphamide or doxyrubicin.
Cancers of the bladder, head and neck, endometrium, small cell carcinoma of the lung, lymphomas and some neoplasms of childhood.

CONTRA-INDICATIONS:
Hypersensitivity to CISPLATIN or any other platinum containing product.
CISPLATIN is contra-indicated in renal or hearing impairment or bone marrow depression.
Pregnancy and lactation.

WARNINGS:
CISPLATIN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
Peripheral blood counts must be monitored closely. Blood counts, at the beginning of therapy and weekly, to assess haematological nadir for dose adjustment are recommended.
Neurological evaluations should also be performed prior to initiation and at periodic intervals during therapy. Treatment should be stopped if signs of peripheral neuropathies, including optic neuritis, papilloedema, cerebral blindness and seizures develop.
Because of cumulative nephrotoxicity, creatinine clearance and serum creatinine concentrations and blood urea should be measured prior to initiation of therapy and before each course of CISPLATIN to detect renal toxicity.
Since ototoxicity is cumulative, an audiometric test must be performed prior to each dose. The concomitant use of other nephrotoxic or ototoxic medicines should be avoided.
Because of the possibility of carcinogenicity and mutagenicity, patients of child bearing age or conceiving potential must exercise non-hormonal conception control.

DOSAGE AND DIRECTIONS FOR USE:
The physician should in all cases be familiar with the current literature before choosing a specific dosage.
CISPLATIN is given by intravenous infusion not more frequently than every 3 to 4 weeks. It is usually given as a single dose of 50 to 120 mg per m² body-surface or in a dose of 15 to 20 mg per m² daily for 5 days.
Subsequent doses should be adjusted according to the nadir of the white-blood cell and platelet counts or before renal function approaches normal. Auditory acuity must also be within normal limits.
Lower doses may be required when CISPLATIN is given as part of a combination regimen and may range from 20 mg per m² upwards every 3 to 4 weeks.
In order to prevent renal toxicity, hydration of the patient is recommended by infusion of 1 to 2 litres of suitable fluid containing 37,5 g mannitol for intravenous infusion for 8 to 12 hours before administration of CISPLATIN. Adequate hydration and urinary output must be maintained before and for 24 hours after administration. Concurrent furosemide may also be used provided that salt and water depletion are avoided.
Any solution not used must be discarded.
Dosage adjustments are needed in cases of impaired renal function, elderly patients or use in combination with other myelosuppressive agents.
Note: CISPLATIN is incompatible with aluminium; do not use needles, intravenous sets or equipment containing aluminium for administration since an interaction may occur and a black precipitate will form.
Guidelines for handling of antineoplastic agents must be followed. Cautious and proper disposal of needles, syringes, containers and unused medication must be done.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Many of the adverse effects of CISPLATIN are an extension of their therapeutic action, which is not selective for malignant cells, but affects all rapidly-dividing cells. In consequence, adverse effects may be expected where normal cell division is fairly rapid, e.g. the bone marrow, lymphoreticular tissue, gastro-intestinal mucosa, skin and gonads, as well as in the foetus.
Serious toxic effects on the kidneys, bone-marrow and ears, occur. These effects are generally dose related and cumulative, and may require dose adjustment.
Haematological effects: Anaemia, leucopenia, thrombocytopenia is the result of dose related and reversible myelosuppression. With leucopenia and thrombocytopenia, the leukocyte and platelet counts reach a nadir between 18 and 23 days after a dose, with recovery within 39 days. Coombs’positive haemolytic anaemia has also been reported.
Nephrotoxicity: Damage to the renal tubules may be evident during the second week after a dose of CISPLATIN. It is generally dose related and cumulative, but may become irreversible at high doses or with repeated treatments and is occasionally fatal.
Intensive hydration may ameliorate nephrotoxic effects.
Electrolyte disturbances, particularly hypomagnesemia and hypocalcemia may occur, possibly as a result of renal tubular damage.
The destruction of large numbers of cells during therapy and the consequent release of breakdown products may also lead to problems with hyperuricaemia and acute renal failure due to uric acid nephropathy.
The concomitant use of other nephrotoxic components should be avoided.
Ototoxicity: It may be more severe in children and it can manifest as tinnitus, loss of hearing in the high frequency range and occasionally deafness or vestibular toxicity.
Gastro-intestinal toxicity: Severe nausea and vomiting occur in most patients 1 to 4 hours after a dose and may persist for up to a week. It may be treated or prevented by antiemetic medication.
Allergic reactions: An allergic reaction can occur within minutes of administration and includes dizziness or fainting, fast heartbeat, swelling of face and wheezing and should be treated with supportive therapy.
Anaphylactic reactions can occur and supportive treatment should be available.
Neurotoxicity: Neurological effects were reported after a single dose or prolonged therapy and may be severe and irreversible.
Peripheral neuropathies, Lhermitte’s sign and autonomic neuropathy have also been reported. Central neurotoxicity includes focal encephalopathy, seizures, aphasia and cortical blindness.
Other: In addition, CISPLATIN is an irritant or vesicant, and produces local pain, irritation, and inflammation at the administration site; extravasation may lead to ulceration and necrosis. Rarely, stomatitis and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported. Loss of appetite has also been reported.
Interactions: Combinations of the following medications may also interact with CISPLATIN, the reaction is dose dependant : Blood dyscrasia causing medications, bone marrow depressants (particularly adriamycin) or radiotherapy, nephrotoxic medication (amino glycoside antibiotics), ototoxic medication, killed virus vaccines. The use of live vaccines is contra-indicated in these patients.
Allopurinol, colchicine, probenecid or sulfinpyrazone can increase the risk of uric acid nephropathy.
Antihistamines, buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes or trimethobenzamide may mask the symptoms of ototoxicity.
CISPLATIN induced renal function impairment may result in bleomycin toxicity.
Furosemide, ethacrinic acid, hydralazine, and propanalol may increase nephrotoxicity.
CISPLATIN is rapidly degraded by bisulphite or metabisulphate and admixtures with preparations containing these as preservatives may result in loss of activity.
Mixtures with sodium bicarbonate, potassium chloride and/or etoposide may cause precipitation of CISPLATIN.
Stability of CISPLATIN when mixed with fluorouracil is limited.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See "Side-effects and Special Precautions".
Treatment should be symptomatic and supportive

IDENTIFICATION:
Clear, colourless to pale yellow liquid, free from particles.

PRESENTATION:
P&U CISPLATIN CSV 10 mg/10 mL INJECTION: Cartons with 5 x 10 mL single dose plastic vials, each containing 1 mg CISPLATIN per mL solution.
P&U CISPLATIN CSV 50 mg/50 mL INJECTION: A single dose plastic vial containing 1 mg CISPLATIN per mL solution.
P&U CISPLATIN CSV 100 mg/100 mL INJECTION: A single dose plastic vial containing 1 mg CISPLATIN per mL solution.

STORAGE INSTRUCTIONS:
Store at room temperature below 25°C. Do not refrigerate. Protect from light.
Any unused portion must be discarded.
Keep out of reach of children.

REGISTRATION NUMBERS:
P&U CISPLATIN CSV 10 mg/10 mL INJECTION: 30/26/0328
P&U CISPLATIN CSV 50 mg/50 mL INJECTION: 30/26/0329
P&U CISPLATIN CSV 100 mg/100 mL INJECTION: 30/26/0330

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
Sandton
2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
June 1997

New addition to this site: February 2005
Source: Pharmaceutical Industry

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