Contraindications: TRISENOX is contraindicated in patients with hypersensitivity to arsenic.

Differentiation Syndrome: In clinical trials, 16-23% of patients treated with TRISENOX for APL developed differentiation syndrome. 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, prednisone prophylaxis is recommended during induction cycle. If differentiation syndrome is suspected, temporarily withhold TRISENOX and immediately initiate dexamethasone 10 mg intravenously twice daily every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for a minimum of 3 days.

Cardiac Conduction Abnormalities: 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 co-administered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).

Encephalopathy: 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 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.

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 0-14 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.

Carcinogenesis: The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Embryo-Fetal Toxicity: TRISENOX can cause fetal harm when administered to a pregnant woman. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Conduct pregnancy testing prior to initiating treatment and advise pregnant women of the potential risk to a fetus. Advise patients of reproductive potential to use effective contraception during treatment with TRISENOX and 6 months after last dose in females and 3 months after last dose in males. TRISENOX may also impair fertility in males.

Lactation: TRISENOX is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child advise women not to breastfeed during treatment with TRISENOX and for two weeks after the final dose.

Patients with Renal Impairment: : Exposure of arsenic trioxide may be higher in patients with severe renal impairment. Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) frequently for toxicity; a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied.

Patients with Hepatic Impairment: Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. Monitor patients with severe hepatic impairment (Child-Pugh Class C) frequently for toxicity.

Most Common Adverse Reactions: The most common adverse reactions (> 30%) were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus.

Please see full Prescribing Information for TRISENOX, including Boxed Warnings.