Cisplatin

WARNING: NEPHROTOXICITY, PERIPHERAL NEUROPATHY, NAUSEA AND VOMITING and MYELOSUPPRESSION. Nephrotoxicity: cisplatin injection can cause severe renal toxicity, including acute renal failure. Severe renal toxicities are dose-related and cumulative. Ensure adequate hydration and monitor renal function and electrolytes. Consider dose reductions or alternative treatments in patients with renal impairment [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 )]. Peripheral Neuropathy: cisplatin injection can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug [see Warnings and Precautions ( 5.2 )]. Nausea and Vomiting: cisplatin injection can cause severe nausea and vomiting. Use highly effective antiemetic premedication [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )]. Myelosuppression: cisplatin injection can cause severe myelosuppression with fatalities due to infections. Monitor blood counts accordingly. Interruption of therapy may be required [see Warnings and Precautions ( 5.4 )]. WARNING: NEPHROTOXICITY, PERIPHERAL NEUROPATHY, NAUSEA AND VOMITING, and MYELOSUPPRESSION See full prescribing information for complete boxed warning. Nephrotoxicity: cisplatin injection can cause severe renal toxicity, including acute renal failure. Ensure adequate hydration. Consider dose reductions or alternative treatments in patients with renal impairment. ( 2.1 , 5.1 ) Peripheral Neuropathy: cisplatin injection can cause dose-related peripheral neuropathy. ( 5.2 ) Nausea and Vomiting: cisplatin injection can cause severe nausea and vomiting. Premedicate with antiemetics. ( 2.1 , 5.3 ) Myelosuppression: cisplatin injection can cause severe myelosuppression with fatalities due to infections. Monitor blood counts and interrupt therapy accordingly. ( 5.4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions: Anaphylaxis and death may occur; monitor for and treat accordingly ( 5.5 ) Ototoxicity: Cumulative toxicity may be severe particularly in pediatric patients; consider audiometric and vestibular function monitoring ( 5.6 , 8.4 ) Ocular toxicity: Optic neuritis, papilledema, and cortical blindness may occur ( 5.7 ) Secondary leukemia: Secondary acute leukemia may occur ( 5.8 ) Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.9 , 8.1 , 8.3 ) 5.1 Nephrotoxicity Cisplatin injection can cause dose-related nephrotoxicity, including acute renal failure that becomes more prolonged and severe with repeated courses of the drug. Renal toxicity typically begins during the second week after a dose of cisplatin injection. Patients with baseline renal impairment, geriatric patients, patients who are taking other nephrotoxic drugs, or patients who are not well hydrated may be more susceptible to nephrotoxicity [see Use in Specific Populations ( 8.5 , 8.6 )] . Ensure adequate hydration before, during, and after cisplatin injection administration [see Dosage and Administration ( 2.1 )] . Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes including magnesium prior to initiating therapy, and as clinically indicated. Consider magnesium supplementation as clinically needed. Consider alternative treatments or reduce the dose of cisplatin injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with cisplatin injection according to clinical treatment guidelines [see Dosage and Administration( 2.5 )]. 5.2 Peripheral Neuropathy Cisplatin injection can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug. Neurologic symptoms have been reported to occur after a single dose. Neuropathy can also have a delayed onset from 3 to 8 weeks after the last dose of cisplatin injection. Manifestations include paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. The neuropathy may progress further even after stopping treatment. Peripheral neuropathy may be irreversible in some patients. Perform a neurological examination before initiating cisplatin injection, at appropriate intervals during therapy, and after completion of therapy. Consider discontinuation of cisplatin injection for patients who develop symptomatic peripheral neuropathy. Geriatric patients may be more susceptible to peripheral neuropathy [see Use in Specific Populations ( 8.5 )] . 5.3 Nausea and Vomiting Cisplatin injection is a highly emetogenic antineoplastic agent. Premedicate with anti-emetic agents [see Dosage and Administration ( 2.1 )] . Without antiemetic therapy, 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 72 hours. Maximal intensity occurs 48 to 72 hours after administration. 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. Consider the use of additional anti-emetics following infusion. 5.4 Myelosuppression Myelosuppression suppression occurs in 25% to 30% of patients treated with cisplatin injection. Fever and infection have been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Geriatric patients may be more susceptible to myelosuppression [see Use in Specific Populations ( 8.5 )] . Perform standard hematologic tests before initiating cisplatin injection, before each subsequent course, and as clinically indicated. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with cisplatin injection. For patients who develop severe myelosuppression during treatment with cisplatin injection, consider dose modifications and manage according to clinical treatment guidelines. 5.5 Hypersensitivity Reactions Cisplatin injection can cause severe hypersensitivity reactions, including anaphylaxis and death. Manifestations have included facial edema, wheezing, tachycardia, and hypotension. Hypersensitivity reactions have occurred within minutes of administration to patients with prior exposure tocisplatin injection. Monitor patients receiving cisplatin injection for possible hypersensitivity reactions. Ensure supportive equipment and medications are available to treat severe hypersensitivity reactions. Severe hypersensitivity reactions require immediate discontinuation of cisplatin injection and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with cisplatin injection [see Contraindications ( 4 )] . Cross-reactivity between platinum-based antineoplastic agents has been reported. Cases of severe hypersensitivity reactions have recurred after rechallenging patients with a different platinum agent. 5.6 Ototoxicity Cisplatin injection can cause ototoxicity, which is cumulative and may be severe. Consider audiometric and vestibular function monitoring. Ototoxicity is manifested by tinnitus, hearing loss in the high frequency range (4,000 to 8,000 Hz) and/or decreased ability to hear normal conversational tones. Ototoxicity can occur during or after treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin injection has been reported. Vestibular toxicity has also been reported. Ototoxic effects can be more severe and detrimental in pediatric patients, particularly in patients less than 5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 40-60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment with other ototoxic drugs and renal impairment. Consider audiometric and vestibular testing in all pediatric patients receiving cisplatin [see Use in Specific Populations ( 8.4 )]. Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may also contribute to the cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs. 5.7 Ocular Toxicity Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving standard recommended doses of cisplatin injection. Blurred vision and altered color perception have been reported after the use of regimens with higher doses and dose frequencies of cisplatin injection. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. Improvement and/or total recovery usually occurs after discontinuing cisplatin injection but can be delayed. 5.8 Secondary Malignancies The development of acute leukemia secondary to the use of cisplatin injection has been reported. In these reports, cisplatin injection was generally given in combination with other leukemogenic agents. 5.9 Embryo-Fetal Toxicity Based on human data, cisplatin injection can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 months after the last dose of cisplatin injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of cisplatin injection [see Use in Specific Populations ( 8.1 , 8.3 )]. 5.10 Injection Site Reactions Injection site reactions can occur during the administration of cisplatin injection. 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. Because of the possibility of extravasation, closely monitor the infusion site during drug administration.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail, in other sections: Nephrotoxicity [see Warnings and Precautions ( 5.1 )] Peripheral Neuropathy [see Warnings and Precautions ( 5.2 )] Nausea and vomiting [see Warnings and Precautions ( 5.3 )] Myelosuppression [see Warnings and Precautions ( 5.4 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] Ototoxicity [see Warnings and Precautions ( 5.6 ] Ocular toxicity [see Warnings and Precautions ( 5.7 )] Secondary malignancies [see Warnings and Precautions ( 5.8 )] Injection site reactions [see Warnings and Precautions ( 5.10 )] Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting myelosuppression, and ototoxicity. The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Blood and lymphatic system disorders: Coombs‑positive hemolytic anemia. hemolytic uremic syndrome, thrombotic thrombocytopenic purpura Cardiovascular disorders: Venous thromboembolism, arterial thromboembolism, myocardial infarction, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, pericardial effusion, cardiac failure, ventricular dysfunction, Raynaud’s phenomenon Eye disorders: Optic neuritis, papilledema, cortical blindness, blurred vision, color blindness, retinal pigmentation Gastrointestinal disorders: Nausea, vomiting, anorexia, diarrhea, stomatitis, gastrointestinal perforation, pancreatitis, hiccups General disorders: Asthenia, malaise Hepatobiliary disorders: Elevations of aminotransferases, lactate dehydrogenase, and bilirubin; hepatic failure Hypersensitivity: Anaphylaxis, facial edema, wheezing, tachycardia, and hypotension Local Site Reactions: Tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema Metabolism and nutrition disorders: Hypomagnesemia, often requiring magnesium supplementation; hyperuricemia, other electrolyte abnormalities (hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia), Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase Musculoskeletal disorders: Muscle cramps (localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration) Nervous system disorders: Peripheral neuropathy, Encephalopathy, loss of motor function, loss of taste, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, progressive multifocal leukoencephalopathy, seizures, Lhermitte’s sign, dorsal column myelopathy, autonomic neuropathy, seizures, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia) Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity Renal and urinary disorders: Nephrotoxicity including renal failure, renal electrolyte wasting, azotemia, decreased creatinine clearance Respiratory disorders: pneumonitis/interstitial lung disease, pulmonary embolism Skin and subcutaneous tissue disorders: Alopecia, rash Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting, myelosuppression, and ototoxicity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .