trisenox

Important safety information

Hepatotoxicity : Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold TRISENOX for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution.( 2.3 , 5.4 ) Carcinogenesis : Arsenic trioxide is a human carcinogen. Monitor patients for the development of second primary malignancies. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Differentiation Syndrome Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with TRISENOX. In clinical trials, 16-23% of patients treated with TRISENOX for APL developed differentiation syndrome. Signs and symptoms include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction. Differentiation syndrome has been observed with and without concomitant leukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. When TRISENOX is used in combination with tretinoin, prophylaxis with prednisone is recommended during the induction cycle [see Dosage and Administration ( 2.1 )] . If differentiation syndrome is suspected, temporarily withhold TRISENOX and immediately initiate dexamethasone 10 mg intravenously every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for a minimum of 3 days [see Dosage and Administration ( 2.3 )] . 5.2 Cardiac Conduction Abnormalities Patients treated with TRISENOX can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trials of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin, 11% experienced QTc (Framingham formula) prolongation > 450 msec for men and > 460 msec for women throughout the treatment cycles. In the clinical trial of patients with relapsed or refractory APL treated with TRISENOX monotherapy, 40% had at least one ECG tracing with a QTc interval greater than 500 msec. A prolonged QTc was observed between 1 and 5 weeks after start of TRISENOX infusion, and it usually resolved by 8 weeks after TRISENOX infusion. There are no data on the effect of TRISENOX on the QTc interval during the infusion of the drug. The risk of torsade de pointes is related to the extent of QTc prolongation, concomitant administration of QTc prolonging drugs, a history of torsade de pointes, pre-existing QTc interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. The risk may be increased when TRISENOX is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) [see Drug Interactions ( 7 )] . Prior to initiating therapy with TRISENOX, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with a ventricular arrhythmia or prolonged QTc. If possible, discontinue drugs that are known to prolong the QTc interval. If it is not possible to discontinue the interacting drug, perform cardiac monitoring frequently [see Drug Interactions ( 7 )] . During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Monitor ECG weekly and more frequently for clinically unstable patients. For patients who develop a QTc Framingham greater than 450 msec for men or greater than 460 msec for women, withhold TRISENOX and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume TRISENOX at a reduced dose [see Dosage and Administration ( 2.3 )] . 5.3 Encephalopathy Serious encephalopathies were reported in patients receiving TRISENOX. Monitor patients for neurological symptoms, such as confusion, decreased level of consciousness, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction. Advise patients and caregivers of the need for close observation. Wernicke’s Encephalopathy Wernicke’s encephalopathy occurred in patients receiving TRISENOX. Wernicke’s encephalopathy is a neurologic emergency that can be prevented and treated with thiamine. Consider testing thiamine levels in patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide). Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving TRISENOX. If Wernicke’s encephalopathy is suspected, immediately interrupt TRISENOX and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. 5.4 Hepatotoxicity In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of TRISENOX and/or tretinoin. Long-term liver abnormalities can occur in patients with APL treated with TRISENOX in combination with tretinoin. In a published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at a median of 7 years (range 0 to 14 years) after treatment with arsenic trioxide in combination with tretinoin. During treatment with TRISENOX, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold TRISENOX and/or tretinoin if elevations in AST or alkaline phosphatase occur to greater than 5 times the upper limit of normal and/or elevation in serum total bilirubin occurs to greater than 3 times the upper limit of normal and resume at reduced dose upon resolution [see Dosage and Administration ( 2.3 )] . 5.5 Carcinogenesis The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies. 5.6 Embryo-Fetal Toxicity TRISENOX can cause fetal harm when administered to a pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/m 2 basis. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRISENOX and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TRISENOX and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .