to local treatments, such as surgery and/or radiotherapy.

o been reported. anaphylactic-like reactions to cisplatin have been reported. these reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines. cisplatin can commonly cause ototoxicity which is cumulative and may be severe. audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug (see adverse reactions ). all pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy. cisplatin can cause fetal harm when administered to a pregnant woman. cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. in mice cisplatin is teratogenic and embryotoxic. if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. patients should be advised to avoid becoming pregnant. the carcinogenic effect of cisplatin was studied in bd ix rats. cisplatin was administered intraperitoneally (i.p.) to 50 bd ix rats for 3 weeks, 3 x 1 mg/kg body weight per week. four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma. the development of acute leukemia coincident with the use of cisplatin has been reported. in these reports, cisplatin was generally given in combination with other leukemogenic agents. injection site reactions may occur during the administration of cisplatin (see adverse reactions ). given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. a specific treatment for extravasation reactions is unknown at this time.

of cyclophosphamide, refer to the cyclophosphamide package insert. in combination therapy, cisplatin injection and cyclophosphamide are administered sequentially. as a single agent, cisplatin injection should be administered at a dose of 100 mg/m 2 iv per cycle once every four weeks. advanced bladder cancer cisplatin injection should be administered as a single agent at a dose of 50 to 70 mg/m 2 iv per cycle 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/m 2 per cycle repeated every 4 weeks is recommended. all patients pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin injection dose is recommended. the drug is then diluted in 2 liters of 5% dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period. if diluted solution is not to be used within 6 hours, protect solution from light. do not dilute cisplatin injection in just 5% dextrose injection. adequate hydration and urinary output must be maintained during the following 24 hours. a repeat course of cisplatin injection 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/mm 3 , wbc ≥4000/mm 3 ). subsequent doses of cisplatin injection should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m 2 , and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 hz). the prevelance of hearing loss in children is particularly high and is estimated to be 40-60%. decreased ability to hear normal conversational tones may occur. deafness after the initial dose of cisplatin has been reported. ototoxic effects may be more severe in children receiving cisplatin. hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. it is unclear whether cisplatin-induced ototoxicity is reversible. vestibular toxicity has also been reported. ototoxic effects may be related to the peak plasma concentration of cisplatin. ototoxicity can occur during treatment or be delayed. audiometric monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy. the risk of ototoxicity may be increased by prior or simultaneous cranial irradiation, and may be more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs (e.g. aminoglycosides and vancomycin), and in patients with renal impairment. genetic factors (e.g. variants in the thiopurine s-methyltransferase [tpmt] gene) may contribute to cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs. hematologic myelosuppression occurs in 25% to 30% of patients treated with cisplatin. 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 (>50 mg/m 2 ). anemia (decrease of 2 g hemoglobin/100 ml) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. fever and infection have also been reported in patients with neutropenia. potential fatalities due to infection (secondary to myelosuppression) have been reported. elderly patients may be more susceptible to myelosuppression (see precautions, geriatric use ). in addition to anemia secondary to myelosuppression, a coombs' positive hemolytic anemia has been reported. in the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician. the development of acute leukemia coincident with the use of cisplatin has been reported. in these reports, cisplatin was generally given in combination with other leukemogenic agents. gastrointestinal marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be so severe that the drug must be discontinued. nausea and vomiting may begin within 1 to 4 hours after treatment and last up to 24 hours. various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment. delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin therapy. diarrhea has also been reported. to report suspected adverse reactions, contact wg critical care, llc at 1-866-562-4708 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

proteins, accounts for the instability of cisplatin in biological matrices. the ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m 2 . cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. however, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. the complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. following cisplatin doses of 20 to 120 mg/m 2 , the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. platinum is present in tissues for as long as 180 days after the last administration. with the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. different metastatic sites in the same patient may have different platinum concentrations. hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m 2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days. over a dose range of 40 to 140 mg cisplatin/m 2 given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. over five days following administration of 40 to 100 mg/m 2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m 2 /day. only a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours. platinum-containing species excreted in the urine are the same as those found following the incubation of cisplatin with urine from healthy subjects, except that the proportions are different. the parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m 2 . the mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 ml/min/m 2 following administration of 100 mg/m 2 as 2-hour or 6- to 7-hour infusions, respectively. the renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. the renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption. there is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis. no significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance. although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.