Arsenic Trioxide
TRISENOX® (arsenic trioxide) injection, for intravenous use only; product label, June 2010. Manufactured for Cephalon Inc., Frazer, PA
WARNINGS
Experienced Physician and Institution: TRISENOX (arsenic trioxide) injection should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia
APL Differentiation Syndrome: Some patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intraVENously BID) should be immediately initiated, irrespective of the leukocyte count, and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome
ECG Abnormalities: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic trioxide
ECG and Electrolyte Monitoring Recommendations: Prior to initiating therapy with TRISENOX, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed; preexisting electrolyte abnormalities should be corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations should be kept above 4 mEq/L and magnesium concentrations should be kept above 1.8 mg/dL. Patients who reach an absolute QT interval value >500 msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. If syncope, rapid or irregular heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, TRISENOX therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc interval during the infusion
Boxed Warning for "Trisenox® (arsenic trioxide) injection, For Intravenous Use Only"; June 2010 product label; Cephalon Inc., Frazer, PA
Product Identification, Preparation, Storage, and Stability
Trisenox® is packaged in 10-mL, glass, single-use ampules containing 10 mg of arsenic trioxide (1 mg/mL). NDC 63459-600-10 (package of 10 ampules)
Trisenox® is formulated as a sterile, nonpyrogenic, clear, colorless, preservative-free solution of arsenic trioxide in water for injection. Sodium hydroxide and hydrochloric acid are used to adjust the pH to 7.5–8.5
Store intact ampules at 25°C (77°F). Temperature excursions are permitted to 15°–30°C (59°–86°F)
Dilute arsenic trioxide in 100–250 mL of 0.9% NS or D5W immediately after withdrawing the drug product from an ampule. Unused drug should be discarded in a manner appropriate for hazardous drugs
Diluted arsenic trioxide solutions are chemically and physically stable for 24 hours when stored at room temperature and for up to 48 hours under refrigeration
Selected incompatibility:
Arsenic trioxide should not be mixed with other drugs
Recommendations for Drug Administration and Ancillary Care
General:
See Chapter 41 for recommended use in renal and hepatic dysfunction
Administer arsenic trioxide by intraVENous infusion over 1–2 hours. The duration of administration may be extended to 4 hours for patients who experience acute vasomotor reactions
A central VAD is not required for administering arsenic trioxide
ECG changes:
QT/QTc prolongation should be expected during treatment with arsenic trioxide, and torsade de pointes and complete heart block have been reported
In >460 ECG tracings from 40 patients evaluated for QTc prolongation, 16 patients (40%) demonstrated at least 1 QTc interval >500 msec
QTc prolongation was observed between 1 and 5 weeks after arsenic trioxide administration, and then returned towards baseline by the end of 8 weeks after arsenic trioxide administration
Neither sex nor age factors correlated with QT prolongation events
Complete AV block has also been reported in association with arsenic trioxide treatment, including a case in a patient with acute promyelocytic leukemia