FDA label 900bbcdc-239f-4fd4-a26e-daf04ea74e79

WARNING Cisplatin injection 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 Cisplatin injection 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 Cisplatin injection have been reported. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of Cisplatin injection administration. Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms (see WARNINGS and ADVERSE REACTIONS sections). Exercise caution to prevent inadvertent Cisplatin injection 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 Cisplatin injection overdose due to confusion with carboplatin or prescribing practices that fail to differentiate daily doses from total dose per cycle.

WARNINGS Cisplatin injection 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 injection 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 injection 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 injection have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to Cisplatin injection, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines. Cisplatin injection 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. Cisplatin injection can cause fetal harm when administered to a pregnant woman. Cisplatin injection is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice Cisplatin injection 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 injection was studied in BD IX rats. Cisplatin injection 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 injection has been reported. In these reports, Cisplatin injection was generally given in combination with other leukemogenic agents. Injection site reactions may occur during the administration of Cisplatin injection (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 injection. 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 injection 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 injection 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 Cisplatin injection 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 injection has been reported. Ototoxic effects may be more severe in children receiving Cisplatin injection. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether Cisplatin injection 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 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 Cisplatin injection. 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 injection has been reported. In these reports, Cisplatin injection was generally given in combination with other leukemogenic agents. Gastrointestinal Marked nausea and vomiting occur in almost all patients treated with Cisplatin injection, 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 injection therapy. Diarrhea has also been reported. OTHER TOXICITIES Vascular toxicities coincident with the use of Cisplatin injection in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud’s phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without Cisplatin injection. It has been suggested that hypomagnesemia developing coincident with the use of Cisplatin injection may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors. Serum Electrolyte Disturbances Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with Cisplatin injection and are probably related to renal tubular damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing Cisplatin injection. Inappropriate antidiuretic hormone syndrome has also been reported. Hyperuricemia Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine. It is more pronounced after doses greater than 50 mg/m 2 , and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels. Neurotoxicity See WARNINGS Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of Cisplatin injection neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of Cisplatin injection. Cisplatin injection therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS : Geriatric Use ). Lhermitte's sign, dorsal column myelopathy, and autonomic neuropathy have also been reported. Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported. Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of Cisplatin injection and with a relatively advanced symptomatic stage of peripheral neuropathy. Ocular Toxicity Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of Cisplatin injection. Improvement and/or total recovery usually occurs after discontinuing Cisplatin injection. Steroids with or without mannitol have been used; however, efficacy has not been established. Blurred vision and altered color perception have been reported after the use of regimens with higher doses of Cisplatin injection or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area. Anaphylactic-Like Reactions Anaphylactic-like reactions have been reported in patients previously exposed to Cisplatin injection. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving Cisplatin injection should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication. Hepatotoxicity Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with Cisplatin injection administration at the recommended doses. Other Events Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported. Local soft tissue toxicity has been reported following extravasation of Cisplatin injection. Severity of the local tissue toxicity appears to be related to the concentration of the Cisplatin injection solution. Infusion of solutions with a Cisplatin injection concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.