FDA label 7cf04f31-8c85-5b93-e053-2991aa0a1eb7

WARNING PLATINOL (cisplatin for injection, USP) should be administered 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. Cumulative renal toxicity associated with PLATINOL is severe. Other major dose-related toxicities are myelosuppression, nausea, and vomiting. Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus, and/or loss of high frequency hearing and occasionally deafness, is significant. Anaphylactic-like reactions to PLATINOL have been reported. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of PLATINOL administration. Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms (see WARNINGS and ADVERSE REACTIONS ). Exercise caution to prevent inadvertent PLATINOL overdose. Doses greater than 100 mg/m 2 /cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid inadvertent PLATINOL overdose due to confusion with PARAPLATIN ® (carboplatin) or prescribing practices that fail to differentiate daily doses from total dose per cycle.

WARNINGS PLATINOL (cisplatin for injection, USP) 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, PLATINOL 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 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. 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 PLATINOL have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to PLATINOL, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines. PLATINOL 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 ). Certain genetic variants in the thiopurine S-methyltransferase (TPMT) gene are associated with increased risk of ototoxicity in children administered conventional doses of cisplatin (see CLINICAL PHARMACOLOGY ). Children who do not have one of these TPMT gene variants remain at risk for ototoxicity. All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy. PLATINOL can cause fetal harm when administered to a pregnant woman. PLATINOL is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice PLATINOL 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 PLATINOL was studied in BD IX rats. PLATINOL 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 PLATINOL has been reported. In these reports, PLATINOL was generally given in combination with other leukemogenic agents. Injection site reactions may occur during the administration of PLATINOL (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 PLATINOL. 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 PLATINOL 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 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 utilization of these procedures. Ototoxicity Ototoxicity has been observed in up to 31% of patients treated with a single dose of PLATINOL 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 PLATINOL has been reported. 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 cisplatin doses. It is unclear whether PLATINOL-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. Variants in the thiopurine S-methyltransferase gene (TPMT) have been reported to be associated with an increased risk of ototoxicity in children treated with cisplatin (see CLINICAL PHARMACOLOGY ). Other genetic factors may also contribute to the cisplatin-induced ototoxicity. Hematologic 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 (>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 PLATINOL has been reported. In these reports, PLATINOL was generally given in combination with other leukemogenic agents. Gastrointestinal Marked nausea and vomiting occur in almost all patients treated with PLATINOL, 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 PLATINOL therapy. Diarrhea has also been reported.