INFORMATION FOR HEALTH PROFESSIONALS
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A sterile, isotonic, preservative-free solution containing cisplatin USP 1mg/mL, sodium chloride BP 9mg/mL and mannitol BP 1mg/mL in water for injections BP.
Cisplatin is an antineoplastic agent. Cisplatin is a platinum compound of which only the cis-isomer is active. It appears to produce intra- and interstrand cross links which modify DNA structure and inhibit DNA synthesis. In addition and to a lesser extent cisplatin inhibits protein and RNA synthesis. It does not appear to be phase-specific in the cell cycle.
Distribution: Cisplatin seems to concentrate in the liver and kidneys. It does not cross the blood brain barrier so does not penetrate the CSF to any great extent.
Elimination and Excretion: After IV injection, plasma decay is biphasic. The initial phase is rapid with a half-life of 25-49 minutes and this is followed by a prolonged elimination phase with a half-life of 2-4 days. This long elimination phase is probably due to a high degree of protein binding. Normally more than 90% is bound to plasma proteins, but this may be more during a slow infusion. Excretion is predominantly renal. About 15-25% of a dose is rapidly excreted, mainly as intact drug, in the first 2-4 hours and 20-75% in the first 24 hours. The remainder represents drug bound to tissues or plasma proteins.
Cisplatin may be used singly or in combination with other chemotherapeutic agents in the treatment of:
Adult and Children Single Agent Therapy: Typical doses and schedules are: 50-100mg/m² as a single IV infusion every 3 to 4 weeks over 6-8 hours or slow IV infusion of 15-20mg/m² for 5 days, every 3 to 4 weeks.
Dosage should be reduced in patients with depressed bone marrow function.
Combination Therapy: Cisplatin is commonly used in combination therapy with the following cytotoxic agents:
Subsequent Treatment with Cisplatin: A repeat course of cisplatin should not be given until:
A base line audiogram should be taken and the patient monitored periodically for auditory deterioration.
With Impaired Liver Function: Human studies show a high uptake of cisplatin in the liver. An elevated AST and alkaline phosphatase with clinical signs of liver toxicity has been reported. Cisplatin should be used with caution in patients with pre-existing hepatic dysfunction.
With Impaired Renal Function: Cisplatin displays high tissue uptake in the kidneys and exhibits dose related and cumulative nephrotoxicity. It is excreted mainly in the urine. The plasma elimination half-life of cisplatin is prolonged and plasma levels are markedly elevated in renal failure.
Caution should be exercised in patients with pre-existing renal dysfunction. Cisplatin is contraindicated in patients with serum creatinine levels greater than 0.2mmol/L. Repeat courses are not advised until serum creatinine is below 140 micromol/L and/or blood urea below 9mmol/L.
Patients should be adequately hydrated before and for 24 hours following administration of cisplatin to ensure good urinary output and minimise nephrotoxicity.
Cisplatin is contraindicated in patients with severe renal impairment, generalised infections, in pregnancy or lactation and in patients with a history of hypersensitivity to Cisplatin or platinum containing compounds.
Special warnings apply to the following areas.
Renal function. Cisplatin produces cumulative nephrotoxicity. Renal function and serum electrolyte (magnesium, sodium, potassium and calcium) should be evaluated prior to initiating cisplatin treatment and prior to each subsequent course of therapy. To maintain urine output and reduce renal toxicity it is recommended that cisplatin be administered as an intravenous infusion over 6 to 8 hours. Moreover, pre-treatment intravenous hydration with 1-2 litres of fluid over 8-12 hours followed by adequate hydration for the next 24 hours is recommended.
Repeat courses of cisplatin should not be given unless the level of serum creatinine is below 1.5 mg/100 mL or the BUN is below 25 mg/100 mL.
Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs (see also 'Interactions').
Bone marrow function. Peripheral blood counts should be monitored frequently in patients receiving cisplatin. Although the hematologic toxicity is usually moderate and reversible, severe thrombocytopenia and leukopenia may occur. In patients who develop thrombocytopenia special precautions are recommended: care in performing invasive procedures; search for signs of bleeding or bruising; test of urine, stools and emesis for occult blood; avoiding aspirin and other NSAIDs. Patients who develop leukopenia should be observed carefully for signs of infection and might require antibiotic support and blood product transfusions.
Hearing function. Cisplatin may produce cumulative ototoxicity, which is more likely to occur with high-dose regimens. Audiometry should be performed prior to initiating therapy, and repeated audiograms should be performed when auditory symptoms occur or clinical hearing changes become apparent. Clinically important deterioration of auditive function may require dosage modifications or discontinuation of therapy.
CNS functions. Cisplatin is known to induce neurotoxicity; therefore, neurologic examination is warranted in patients receiving a cisplatin-containing treatment. Since neurotoxicity may result in irreversible damage, it is recommended to discontinue therapy with cisplatin when neurologic toxic signs or symptoms become apparent.
In addition, patients receiving cisplatin should be observed for possible anaphylactoid reactions, and appropriate equipment and medication should be readily available to treat such reactions.
Nausea and Vomiting: Marked nausea and vomiting occur in almost all patients treated with cisplatin and are occasionally so severe that dosage reduction or discontinuance of treatment is necessary.
Cisplatin should be administered only by physicians experienced in the use of chemotherapeutic agents. To minimise the risk of nephrotoxicity hydrate before, during and after therapy (see Dosage and Administration).
Use in Prenancy and Lactation: The safety of cisplatin in pregnancy has not been established. Cisplatin can cross the placental barrier. Cisplatin has been shown to be teratogenic, embryotoxic and carcinogenic in mice and embryotoxic and leukemogenic in rats. Therefore cisplatin is considered to be potentially harmful to the foetus when administered to a pregnant woman. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant during cisplatin therapy.
Males undergoing cisplatin treatment should use barrier contraceptive measures.
It is not clearly established whether cisplatin is excreted in human milk, but limited data suggest that distribution into milk does not occur. However, because of the potential for serious adverse reactions in infants should the drug pass into the milk, breast-feeding is not recommended during therapy.
Carcinogenicity: Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seems to indicate that the carcinogenic risk is greatest with the alkylating agents.
Mutagenicity: Cisplatin is mutagenic in bacteria and has been shown to cause chromosome aberrations in animal cells in tissue culture.
Use in Children: Ototoxic effects of cisplatin may be more severe in children.
Use in Elderly: No geriatrics-specific information is available on the use of cisplatin in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving cisplatin.
Dental: The bone marrow depressant effects of cisplatin may result in an increased incidence of microbial infection, delayed heating, and gingival bleeding. Dental work, wherever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal.
Cisplatin may also rarely cause stomatitis with considerable discomfort.
Severe nausea and vomiting usually begins 1-4 hours after treatment and may persist for up to a week. This may necessitate stopping treatment.
Nephrotoxicity. Acute renal toxicity, which was highly frequent in the past and represented the major dose-limiting toxicity of cisplatin, has been greatly reduced by the use of 6 to 8-hour infusions as well as by concomitant intravenous hydration and forced diuresis. Cumulative toxicity, however, remains a problem and may be severe. Renal impairment, which is associated with tubular damage, may be first noted during the second week after a dose and is manifested by an increase in serum creatinine, BUN, serum uric acid and/or a decrease in creatinine clearance. Renal insufficiency is generally mild to moderate and reversible at the usual doses of the drug (recovery occurring as a rule within 2-4 weeks); however, high or repeated cisplatin doses can increase the severity and duration of renal impairment and may produce irreversible renal insufficiency (sometimes fatal). Renal failure has been reported also following intraperitoneal instillation of the drug.
Cisplatin may also cause serious electrolyte disturbances, mainly represented by hypomagnesemia, hypocalcemia, and hypokalemia, and associated with renal tubular dysfunction. Hypomagnesemia and/or hypocalcemia may become symptomatic, with muscle irritability or cramps, clonus, tremor, carpopedal spasm, and/or tetany.
Gastrointestinal toxicity. Nausea and vomiting occur in the majority of cisplatin-treated patients, usually starting within 1 hour of treatment and lasting up to 24 hours or longer. These side effects are only partially relieved by standard antiemetics. The severity of these symptoms may be reduced by dividing the total dose per cycle into smaller doses given once daily for five days.
Hematologic toxicity. Myelosuppression often occurs during cisplatin therapy, but is mostly mild to moderate and reversible at the usual doses. However, leukopenia and thrombocytopenia are dose-related, and may become clinically relevant in patients receiving high doses of cisplatin or in patients who have received prior myelosuppressive treatments. WBC and platelet nadirs generally occur after about 2 weeks but levels return to pre-treatment values in most patients within 4 weeks. Cisplatin may also induce anaemia: this is not clearly dose-related and is occasionally caused by hemolysis.
There have been rare reports of acute myelogenous leukemias and myelodysplastic syndromes arising in patients who have been treated with cisplatin, mostly when given in combination with other potentially leukemogenic agents.
Ototoxicity. Unilateral or bilateral tinnitus, with or without hearing loss, occurs in about 10% of cisplatin-treated patients and is usually reversible. The damage to the hearing system appears to be dose-related and cumulative, and it is reported more frequently in very young and very old patients
Neurotoxicity. Peripheral neuropathies occur infrequently with usual doses of the drug. These are generally sensory in nature (e.g. paresthesia of the upper and lower extremities) but can also include motor difficulties, reduced reflexes and leg weakness. Autonomic neuropathy, seizures, slurred speech, loss of taste and memory loss have also been reported. These neuropathies usually appear after prolonged therapy, but have also developed after a single drug dose. Peripheral neuropathy may be irreversible in some patients; however, it has been partially or completely reversible in others following discontinuance of cisplatin therapy.
Hypersensitivity. Anaphylactic and anaphylactic-like reactions, such as flushing, facial edema, wheezing, tachycardia and hypotension, have been occasionally reported. These reactions may occur within minutes of cisplatin administration. Rarely, urticarial or maculopapular skin rashes have also been observed.
Ocular toxicity. Optic neuritis, papilledema, and cortical blindness have been reported rarely in patients receiving cisplatin. These events are usually reversible after drug withdrawal.
Hepatotoxicity. Mild and transient elevations of serum AST and ALT levels may occur infrequently.
Other toxicities. Other reported toxicities are: cardiovascular abnormalities (coronary artery disease, congestive heart failure, arrhythmias, postural hypotension, thrombotic microangiopathy, etc), hyperuricemia, hyponatremia/ syndrome of inappropriate antidiuretic hormone (SIADH), mild alopecia, myalgia, pyrexia and gingival platinum line. Pulmonary toxicity has been reported in patients treated with cisplatin in combination with bleomycin or 5-fluorouracil.
Local effects such as phlebitis, cellulitis and skin necrosis (following extravasation of the drug) may also occur.
Cisplatin can affect male fertility: impairment of spermatogenesis and azoospermia have been reported. Although the impairment of spermatogenesis can be reversible, males undergoing cisplatin treatment should be warned about the possible adverse effects on male fertility.
Cisplatin is mostly used in combination with antineoplastic drugs having similar cytotoxic effects. In these circumstances additive toxicity is likely to occur.
Other known drug interactions are reported below.
Acute overdosage with cisplatin may result in an enhancement of its expected toxic effects (eg kidney failure, severe myelosuppression, intractable nausea and vomiting, severe neurosensorial toxicities, liver failure etc.). Death may also occur.
No proven antidotes are known for cisplatin overdosage. Hemodialysis is only effective, even then partially, up to 3 hours after administration because of the rapid and extensive binding of platinum to plasma proteins. Signs and symptoms of overdosage should be managed with supportive measures.
Store below 25°C. Do not refrigerate. Protect from light.
Prescription Medicine.
10mg/10mL, 5's.
50mg/50mL, 1's.
The unopened vials should be stored at controlled room temperature, protected from light.
The reconstituted solution must not be cooled or refrigerated as cooling may result in precipitation; it should be kept at room temperature and protected from light, also during i.v. infusion.
Any unused solution should be discarded.
Cisplatin powder should be dissolved in sterile Water for Injections such that the reconstituted solution contains 1 mg/mL of cisplatin. The reconstituted solution should be diluted in 2 litres of 0.9% saline or a dextrose/saline solution (to which 37.5g of mannitol may be added).
Cisplatin solution for injection should be diluted in 2 litres of 0.9% Sodium Chloride Injection or 5% Dextrose and 0.45% Sodium Chloride Solution.
Personnel should be trained in good technique for reconstitution and handling. Pregnant staff should be excluded from working with cisplatin.
Preparation should be performed in a designated area ideally in a vertical laminar flow hood, with the work surface covered with disposable plastic-backed absorbent paper.
Care should be taken to prevent inhaling particles and exposing the skin to cisplatin.
Adequate protective clothing should be worn, such as PVC gloves, safety glasses, disposable gowns and masks.
It is recommended that leur lock fittings are used in the assembly of syringes and giving sets to avoid leakage.
In the event of contact with the eyes, wash with water or saline; if the skin comes into contact with the drug wash thoroughly with water and in both cases seek medical advice. Seek immediate medical attention if the drug is ingested or inhaled.
All used material, needles, syringes, vials and other items which have come into contact with cytotoxic drugs should be incinerated. Excreta should be similarly treated. Contaminated surfaces should be washed with copious amounts of water.
Pharmacia & Upjohn
PO Box 11-282
Ellerslie
Auckland
New Zealand
Ph: (09) 270-0328
26 April 1999
(Ref: CDS July 1998)