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Platinol ( Cisplatin solution) is a clear colourless sterile aqueous solution of cisplatin 1.0mg/mL in vials containing 10mg, 50mg or 100mg cisplatin for intravenous administration.
Platinol has biochemical properties similar to that of bifunctional alkylating agents producing interstrand and intrastrand crosslinks in DNA. It is apparently cell-cycle non-specific.
Following a single I.V. dose, Platinol concentrates in liver, kidneys, and large and small intestines in animals and humans. Platinol apparently has poor penetration into the CNS. Plasma levels of radioactivity decay in a biphasic manner after an I.V. bolus dose of radioactive Platinol to patients.
Following bolus injection of intravenous infusion over 2 to 7 hours, of doses ranging 50 to 100 mg/m², plasma cisplatin half-life is approximately 30 minutes. The ratios of cisplatin to total, free (ultrafilterable) platinum in the plasma range from 0.5 to 1.1 after a dose of 100 mg/m².
Cisplatin does not undergo instantaneous and reversible binding to plasma proteins characteristic of normal drug-protein binding; however, the platinum from cisplatin becomes bound to plasma proteins. These complexes are slowly eliminated with a half-life of 5 days or more.
Over a range of doses administered as bolus injections or infusions of up to 24 hours, approximately 10 to 40% of the platinum administered is excreted in the urine in 24 hours. Similar mean urinary recoveries of platinum are found following daily administration on five consecutive days. Intact cisplatin accounts for the majority of platinum excreted in the urine within one hour of administration. Renal clearance of cisplatin exceeds creatinine clearance. The renal clearance of free (ultrafilterable) platinum also exceeds creatinine clearance, is non-linear and depends on dose, urine flow rate and individual variability in tubular secretion and reabsorption. No close correlation exists between the renal clearance of either free (ultrafilterable) platinum or cisplatin and creatinine clearance. Mannitol administration increases urinary excretion of Platinol following intravenous infusion and excretion of up to 75% in 24 hours has been reported. There is a potential for accumulation of free (ultrafilterable) platinum in plasma when cisplatin is administered on a daily basis, but not when it is administered on an intermittent basis.
Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, faecal excretion of platinum appears to be insignificant.
Platinol is indicated as palliative therapy to be employed as follows:
In established combination therapy with other approved chemotherapeutic agents in patients with metastatic non-seminomatous germ cell tumours who have already received appropriate surgical and/or radiotherapeutic procedures.
Platinol, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumours refractory to standard chemotherapy who have not previously received Platinol therapy.
Platinol, as a single agent, is indicated as secondary therapy in patients with advanced stage bladder cancer refractory to standard chemotherapy who have not previously received Platinol therapy.
Platinol, as a single agent, is indicated as secondary therapy in patients with squamous cell carcinoma of the head and neck refractory to standard chemotherapy who have not previously received Platinol therapy.
Needles or intravenous sets containing aluminium parts that may come in contact with Platinol should not be used for preparation or administration. Aluminium reacts with Platinol, causing precipitate formation and a loss of potency.
The solution should be used intravenously only and should be administered by I.V. infusion only as recommended below.
The usual dosage of Platinol for the treatment of non-seminomatous carcinoma in combination with other approved therapeutic agents is :
20mg/m² I.V. daily for 5 days (Days 1-5) every three weeks for three courses.
As a single agent, Platinol may be administered at a dose of 100mg/m² I.V. once every 4 weeks.
Platinol should be administered as a single agent at a dose of 50-70 mg/m² I.V. once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m² repeated every 4 weeks is recommended.
As a single agent, Platinol may be administered at a dose of 100mg/m² I.V. once every 4 weeks.
The following important principles should be taken into consideration when administering cisplatin:
A repeat course of Platinol should not be given until the serum creatinine is below 1.5 mg/100 mL and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm³, WBC ≥ 4,000/mm³). Subsequent doses of Platinol should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
Platinol is contraindicated in patients with pre-existing renal impairment. Platinol should not be employed in myelosuppressed patients or patients with hearing impairment.
Platinol is contraindicated in patients with a history of allergic reactions to Platinol or other platinum-containing compounds.
Platinol should be administered only in a hospital 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 diagnostic and treatment facilities are readily available.
Platinol produces cumulative nephrotoxicity. The serum creatinine, BUN, and creatinine clearance should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, Platinol should not be given more frequently than once every 3 to 4 weeks (see Adverse Reactions ).
Anaphylactic-like reactions to Platinol have been reported and include facial oedema bronchorestriction, tachycardia and hypotension. These reactions have occurred within minutes of administration to patients with prior exposure to Platinol, and have been alleviated by administration of adrenaline, corticosteroids and antihistamines.
There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of Platinol or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation.
Loss of motor function has also been reported.
Since ototoxicity of Platinol is cumulative, audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug (see Adverse Reactions ).
Platinol has been found to have a carcinogenic potential in animals. The development of acute leukaemia co-incident with the use of Platinol has been reported rarely in humans. In these reports, Platinol was generally given in combination with other leukaemogenic agents.
Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurological examination should also be performed regularly ( see Adverse Reactions ).
Neurologic examination should also be performed regularly (see Adverse Reactions). Platinol should be administered only in a hospital under the supervision of a qualified physician experienced in the use of cancer chemotherapy agents.
Because of its high protein binding Platinol may interfere with the distribution of other protein bound medications.
As Platinol produces cumulative nephrotoxicity and ototoxicity, other nephrotoxic or ototoxic drugs should be avoided during Platinol therapy unless unavoidable.
Following dilution of the solution Platinol undergoes varying degrees of decomposition, depending on the diluent used. Normal Saline is the preferred diluent (see Dosage and Administration ).
Platinol, like several other cytotoxic agents, is likely to produce foetal damage. Safe use in human pregnancy has not been established. Platinol is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice Platinol is teratogenic and embryotoxic.
It is not known whether Platinol is excreted in breast milk. To avoid possible harm to the baby, breast feeding is not advised during Platinol therapy.
Dose-related and cumulative renal insufficiency is the major dose-limiting toxicity of Platinol. Renal toxicity has been noted in 28 to 36% of patients treated with a single dose of 50mg/m². It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of Platinol can be given. Impairment of renal function has been associated with renal tubular damage. The administration of Platinol using a 6 to 8 hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilisation of these procedures.
Ototoxicity has been observed in up to 31% of patients treated with a single dose of Platinol 50mg/m², and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). Decreased ability to hear normal conversational tones may occur occasionally. Ototoxic effects may be more severe in children receiving Platinol. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses. It is unclear whether Platinol-induced ototoxicity is reversible. Ototoxicity may be enhanced with prior or simultaneous cranial irradiation and may be related to peak plasma concentration of Platinol. Careful monitoring or audiometry should be performed prior to initiation of therapy and prior to subsequent doses of Platinol. Vestibular toxicity has also been reported.
Myelosuppression occurs in 25 to 30% of patients treated with Platinol. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50mg/m²). Anaemia (decrease of >2g haemoglobin/100mL) occurs at approximately the same frequency but with a later onset than leukopenia and thrombocytopenia.
Platinol has been shown to sensitise red blood cells, sometimes resulting in a direct Coombs-positive haemolytic anaemia. The incidence, severity and relative importance of this effect in relation to other haematological toxicity has not been established, but the possibility of a haemolytic process should be considered in any person who is receiving Platinol and has an unexplained fall in haemoglobin. The haemolytic process reverses on cessation of therapy.
The development of acute leukemia coincident with the use of Platinol has been reported rarely in humans. In these reports, Platinol was generally in combination with other leukemogenic agents.
Marked nausea and vomiting occur in almost all patients treated with Platinol, and are occasionally so severe that the drug must be discontinued. Nausea and vomiting usually begin within one to four hours after treatment and last up to 24 hours. Various degrees of nausea and anorexia may persist for up to one week after treatment.
Delayed nausea and vomiting (beginning or persisting 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of Platinol therapy.
Diarrhoea has also been reported.
Neurotoxicity usually characterised by peripheral neuropathies, has occurred in some patients. Loss of taste and seizures have also been reported. Neuropathies resulting from Platinol treatment may occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs usually develop during treatment, rarely they may begin after the last dose of Platinol. The neuropathy may progress after stopping treatment.
Platinol therapy should be discontinued when the symptoms are first observed (paraesthesia of fingers/toes, loss of sensory functions, loss of reflexes). Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. L-Hermitte's sign and autonomic neuropathy have also been reported.
Muscle cramps of sudden onset and short duration have been reported. These were usually reported in patients who had received a relatively high dose of Platinol, and who had a relatively advanced stage of peripheral neuropathy.
Hypomagnesaemia, hypocalcaemia, hyponatraemia, hypokalaemia and hypophosphataemia have been reported to occur in patients with Platinol and are probably related to renal tubular damage. Tetany has occasionally been reported in those patients with hypocalcaemia and hypomagnesaemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing Platinol.
Inappropriate antidiuretic hormone syndrome has also been reported.
Hyperuricaemia has been reported to occur at approximately the same frequency as the increase in BUN and serum creatinine. It is more pronounced after doses greater than 50mg/m², and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricaemia effectively reduces uric acid levels.
Optic neuritis, papilloedema and cerebral blindness have been reported infrequently in patients receiving standard recommended doses of Platinol. Improvement and/or total recovery usually occurs after discontinuing Platinol. Steroids with or without mannitol have been used; however, efficacy has not been established.
Blurred vision and altered colour perception have been reported after the use of regimens with higher doses of Platinol or greater dose frequencies than those recommended. The altered colour perception manifests as a loss of colour discrimination, particularly in blue-yellow axis. The only finding on fundoscopic examination is irregular retinal pigmentation of the macular area.
Anaphylactic-like reactions have been occasionally reported in patients previously exposed to Platinol. The reactions consist of facial oedema, wheezing, tachycardia and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous adrenalin, corticosteroids and antihistamines. Patients receiving Platinol should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.
Transient elevations of hepatic enzymes, and bilirubin can occur when Platinol is administered in recommended doses.
Vascular toxicities coincident with the use of Platinol in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogenous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without Platinol. It has been suggested that hypomagnesaemia developing coincident with the use of Platinol may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesaemia, or a combination of any of these factors.
Other toxicities reported to occur infrequently are cardiac abnormalities, hiccups, elevated serum amylase and rash. Alopecia has also been reported.
Local soft tissue toxicity has rarely been reported following extravasation of Platinol. Infiltrations of solutions of Platinol may result in tissue cellulitis, fibrosis and necrosis.
Plasma levels of anticonvulsants may become subtherapeutic during cisplatin therapy.
In a randomised trial in advanced ovarian cancer, response duration was adversely affected when pyridoxine was used with Altretamine (hexamethylmelamine) and Platinol.
Caution should be used to prevent inadvertent overdosage with Platinol.
Acute overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can occur following overdosage.
No proven antidotes have been established for Platinol overdosage. Haemodialysis even when initiated four hours after overdosage, appears to have little effect on removing platinum from the body because of rapid and high degree of protein binding of Platinol. Management of overdosage should include general supportive measures to sustain the patient through the period of toxicity that may occur.
Unopened vials of Cisplatin solution must be stored in a cool dry place at a temperature between 15 - 25°C (Do not refrigerate. Do not freeze). Protect from light. The recommended storage of unopened vials provides a stable product until the expiration date on the label. Cisplatin solution in 0.9% NaCl; 0.9% NaCl with mannitol and 5% dextrose; 0.9% NaCl and 5% dextrose, and 0.33% NaCl with mannitol and 5% dextrose is stable for 6 to 8 hours at room temperature (25°C).
Once diluted, the solution should be kept at room temperature (25°C). If the diluted solution is refrigerated a precipitate will form.
If the diluted solution is not used within 6 hours, protect the infusion from light.
Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published and should be used appropriately.
As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of Platinol. Skin reactions associated with accidental exposure to Platinol may occur. The use of gloves is recommended. If Platinol solution contacts skin or mucosae, immediately wash the skin or mucosae thoroughly with soap and water.
Prescription Medicine.
Platinol ( Cisplatin ) for injection. Packed in amber vials containing 10mg, 50mg and 100mg of Cisplatin in 10mL, 50mL and 100mL solutions respectively.
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a central atom of platinum surrounded by two chlorine atoms and two ammonia molecules in the cis position. The molecular formula of the active ingredient is PtCl2H6N2, with a molecular weight of 300.1. It is soluble in water or saline at 1mg/mL and in dimethylformamide at 24mg/mL.
Bristol-Myers Squibb (NZ) Ltd
Stanway Business Park
Tower 2, Level 1
646 Great South Road
Ellerslie, AUCKLAND
January 1995
PLATINOL..DOC