Cisplatin

INDICATIONS AND USAGE Cisplatin Injection is indicated as therapy to be employed as follows: Metastatic Testicular Tumors In established combination therapy with other approved chemotherapeutic agents in patients with metastatic testicular tumors who have already received appropriate surgical and/or radio therapeutic procedures. Metastatic Ovarian Tumors In established combination therapy with other approved chemotherapeutic agents in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic procedures. An established combination consists of cisplatin and cyclophosphamide. Cisplatin Injection, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received Cisplatin Injection therapy. Advanced Bladder Cancer Cisplatin Injection is indicated as a single agent for patients with transitional cell bladder cancer which is no longer amenable to local treatments, such as surgery and/or radiotherapy.

DOSAGE AND ADMINISTRATION Cisplatin is administered by slow intravenous infusion. CISPLATIN SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION. Note: Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency. Metastatic Testicular Tumors The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m 2 IV daily for 5 days per cycle. Metastatic Ovarian Tumors The usual cisplatin dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m 2 IV per cycle once every 4 weeks (DAY 1). The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m 2 IV once every 4 weeks (DAY 1). For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert. In combination therapy, cisplatin and cyclophosphamide are administered sequentially. As a single agent, cisplatin should be administered at a dose of 100 mg/m 2 IV per cycle once every 4 weeks. Advanced Bladder Cancer Cisplatin 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 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 hour to 8 hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute cisplatin in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours. A repeat course of cisplatin 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 ≥ 4,000/mm 3 ). Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

CONTRAINDICATIONS Cisplatin is contraindicated in patients with pre-existing renal impairment. Cisplatin should not be employed in myelosuppressed patients, or in patients with hearing impairment. Cisplatin is contraindicated in patients with a history of allergic reactions to cisplatin or other platinum containing compounds.

WARNINGS Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks (see ADVERSE REACTIONS ). Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use ). There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin 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. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS, Geriatric Use ). Loss of motor function has also 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.

ADVERSE REACTIONS Nephrotoxicity Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m 2 . 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 cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use ). Impairment of renal function has been associated with renal tubular damage. The administration of cisplatin using a 6 hour to 8 hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures. Ototoxicity 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 (4,000 to 8,000 Hz). The prevalence of hearing loss in children is particularly high and is estimated to be 40 to 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 hour 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 Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

HOW SUPPLIED CISplatin Injection (1 mg per mL) is supplied as follows: NDC CISplatin Injection (1 mg per mL) Package Factor 25021-253-50 50 mg per 50 mL Multi-Dose Vial 1 vial per carton 25021-253-51 100 mg per 100 mL Multi-Dose Vial 1 vial per carton The above products are multiple dose vials packaged individually. Storage Conditions Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Do not refrigerate. Protect from light. Sterile, Nonpyrogenic, Preservative-free. This container closure is not made with natural rubber latex.