Action And Clinical Pharmacology: Cisplatin is thought to act by producing inter-strand and intra-strand cross-links of cellular DNA in a similar manner to bifunctional alkylating agents. It does not appear to be cell-cycle specific.
Using radioactive platinum, a high uptake of the drug was found in kidneys, liver and intestines with poor penetration of the CNS. An initial plasma half-life of 25 to 49 minutes and a terminal half-life of 58 to 73 hours was calculated. After initial i.v. injection, the radioactive platinum was rapidly cleared from the blood and more than 90% of the radioactive platinum in the post-distribution phase was protein-bound. The radioactive platinum was excreted primarily in the urine but only 27 to 45% of the dose was recovered in the first 5 days after administration. Excretion of platinum is slow and has been detected in tissue samples 4 months after administration.
Indications And Clinical Uses: As palliative therapy, to be employed in addition to other modalities, or in established combination therapy with other chemotherapeutic agents in the following:
Metastatic Testicular Tumors: In patients who have already received appropriate surgical and/or radiotherapeutic and/or chemotherapeutic procedures.
Metastatic Ovarian Tumors: As secondary therapy in patients refractory to standard chemotherapy.
It has also been used in advanced stage and refractory bladder carcinoma and in squamous cell carcinoma of the head and neck.
Contra-Indications: In patients with a history of allergic reaction to cisplatin or other platinum-containing compounds.
The physician should carefully weigh the therapeutic benefit expected versus the risk of toxicity which may occur when cisplatin is used as indicated.
Manufacturers’ Warnings In Clinical States: Caution: Cisplatin is a potent drug and should be used only by physicians experienced with cancer chemotherapy drugs. Blood counts as well as renal and hepatic function tests should be taken regularly. Discontinue the drug if abnormal depression of bone marrow or abnormal renal or hepatic function is seen (see Precautions).
Cisplatin has been shown to be cumulatively ototoxic and should not be given to patients with hearing impairment. It is recommended that hearing functions be monitored prior to and during treatment with cisplatin.
Cisplatin should be used cautiously in individuals with pre-existing renal impairment or with myelosuppressed patients.
Serum creatinine, BUN and creatinine clearance should be measured prior to initiating therapy and should be monitored throughout treatment with cisplatin, as cisplatin produces cumulative nephrotoxicity.
Anaphylactic-type reactions have been reported with cisplatin within minutes of administration to patients who have been previously exposed to cisplatin. The reactions have been alleviated by administration of epinephrine, steroids and antihistamines.
Pregnancy: Safe use in human pregnancy has not been established.
Cisplatin has been shown to be mutagenic in bacteria and to produce chromosome aberrations in animal cells in tissue culture and is teratogenic and embryotoxic in mice. Although cisplatin has not been definitely established as being carcinogenic, compounds with similar mechanisms of action have been reported to be carcinogenic.
Precautions: As with all potent antineoplastic drugs, cisplatin should be administered only by clinicians who are experienced in the use of antineoplastic therapy.
Because of the cumulative renal toxicity of cisplatin, it should not be administered more frequently than once every 3 to 4 weeks. In order to reduce nephrotoxicity, pretreatment hydration with 1 to 2 L of fluid infused over 8 to 12 hours, together with maintenance hydration and urinary output during the 24 hours following administration, is recommended.
Weekly peripheral blood counts should be carried out and liver function should be monitored periodically. As well, neurological examinations should be performed on a regular basis.
Cisplatin is incompatible with i.v. sets, needles and syringes which contain aluminum. In contact with aluminum, a visible black precipitate will form.
Adverse Reactions: Nephrotoxicity: Renal toxicity has been shown to occur in 28 to 36% of patients treated with a single dose of cisplatin at a dose of 50 mg/m Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must be restored to normal before additional cisplatin therapy is given.
Nephrotoxicity is usually seen during the second week after a dose as elevations in BUN, creatinine, serum uric acid and/or a decrease in creatinine clearance.
Renal impairment has been associated with renal tubular damage. The administration of cisplatin with a 6 to 8 hour infusion with i.v. hydration and mannitol diuresis has been used to reduce nephrotoxicity.
Ototoxicity: This has occurred in up to 31% of patients treated with a single 50 mg/mdose of cisplatin. The usual signs of ototoxicity are tinnitus and/or hearing loss in the high frequency range (4 000 to 8 000 Hz). Ototoxicity may be more severe in children and more frequent and severe with repeated administration. Hearing loss can be unilateral or bilateral and may not be reversible.
Hemotoxicity: Myelosuppression is observed in about 30% of patients treated with cisplatin. Changes 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 doses in excess of 50 mg/m Anemia, demonstrated as a decrease of greater than 2 g of hemoglobin/100 mL, occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia.
Gastrointestinal: Most patients treated with cisplatin will demonstrate marked nausea and vomiting which occasionally may be so severe that the drug must be discontinued. Gastrointestinal side effects usually occur 1 to 4 hours after treatment and last up to 24 hours. Various degrees of nausea and anorexia may persist for up to 1 week after treatment.
Hyperuricemia: The incidence of hyperuricemia is approximately the same as for increases in BUN and serum creatinine. The hyperuricemia is more pronounced after doses greater than 50 mg/mand usually peaks 3 to 5 days after the initial dose. Allopurinol may be used to effectively reduce uric acid levels.
Neurotoxicity: Peripheral neuropathies have been reported in some patients following cisplatin administration. Loss of taste and seizures have been reported. Neuropathies may occur after prolonged therapy of 4 to 7 months, however, neurologic symptoms have been reported to occur after a single dose. As preliminary evidence suggests that peripheral neuropathies may be irreversible in some patients, cisplatin therapy should be discontinued when the symptoms are first observed.
Anaphylactic-like Reactions: Anaphylactic-like reactions have occasionally been reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia and hypotension within a few minutes of drug administration. Anaphylactic-like reactions may be controlled by the use of i.v. epinephrine, corticosteroids or antihistamines. Patients receiving cisplatin should be observed carefully for anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication, should it arise.
Other toxicities which have been reported to occur infrequently include cardiac abnormalities, anorexia and elevated AST.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdosage or toxic reactions, symptomatic supportive measures should be taken. Complications to be anticipated include nephrotoxicity, ototoxicity, neurotoxicity and hemotoxicity. Patients should be monitored for 3 to 4 weeks in case of delayed toxicity.
Dosage And Administration: Adults and children 50 to 75 mg/mas a single i.v. dose every 3 to 4 weeks, or 15 to 20 mg/mi.v. daily for 5 days every 3 to 4 weeks (see Administration).
Do not give a repeat course of cisplatin 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 concentration (platelets 100 000/mm WBC 4 000/mm. Do not give subsequent doses of cisplatin until an audiometric analysis indicates that auditory acuity is within normal limits.
When employed in combination with other antitumor drugs, adjust the cisplatin dose appropriately.
Administration: Cisplatin is administered by intravenous infusion after dilution (see Dilution and Guidelines for Safe Handling of Cytotoxic Drugs).
Pretreatment hydration with 1 to 2 L of fluid infused for 8 to 12 hours prior to a cisplatin dose is advised. The diluted drug is then infused over a 6 to 8 hour period. Maintain adequate hydration and urinary output over the next 24 hours.
It is important that none of the injection components such as i.v. needles, syringes or sets have aluminum components, because these are incompatible with cisplatin.
Stability and Storage: Vials of cisplatin injection USP are stored at room temperature between 15 and 25°C. Do not refrigerate or freeze cisplatin solutions since a precipitate will form.
Preparation of I.V. solutions: I.V. needles, syringes, or sets having aluminum components should not be employed in preparation or administration of cisplatin solutions. An interaction will occur between aluminum and platinum from cisplatin causing a black precipitate which is visible in the cisplatin solution.
Dilution: Dilute the prepared cisplatin injection in 2 L of 5% dextrose in one half or one third N saline containing 37.5 g of mannitol.
Diluted cisplatin injection solution is suitable for i.v. infusion. This solution is not preserved; it should be used within 24 hours, and the unused portion discarded after that time, in order to avoid risk of microbial contamination.
Warning: As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used.
Guidelines for Safe Handling of Cytotoxic Drugs: Preparation of all antineoplastic agents should be done in a vertical laminar flow hood, when possible.
Personnel preparing parenteral antineoplastic agents should wear PVC gloves, safety glasses, disposable gowns, and masks.
All needles, syringes, vials, ampuls and other materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1 000°C or more. Sealed containers may explode. If incineration is not available, the waste material should be neutralized, usually with 5% sodium hypochlorite and/or 5% sodium thiosulfate, then placed in sealed containers and deposited in landfill sites, according to local regulations.
Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examination.
Availability And Storage: Cisplatin Injection (0.5 mg/mL): Each mL of sterile, unpreserved solution contains: cisplatin 0.5 mg with sodium chloride 9 mg and mannitol 1 mg in water for injection. Hydrochloric acid is added to adjust the pH. Single dose glass vials of 100 mL containing 50 mg of cisplatin. Do not refrigerate.
Cisplatin Injection (1 mg/mL): Each mL of sterile, unpreserved solution contains: cisplatin 1.0 mg with sodium chloride 9 mg and mannitol 1 mg in water for injection. Hydrochloric acid is added to adjust the pH. Single dose glass vials of 10, 50 and 100 mL containing 10, 50 and 100 mg of cisplatin, respectively. Do not refrigerate.
CISPLATIN INJECTION Faulding Antineoplastic