WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE
APL Differentiation Syndrome: 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. High-dose steroids have
been administered 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), immediately initiate high-dose steroids
(dexamethasone 10 mg intravenously BID), irrespective of the leukocyte count, and
continue 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.
Cardiac Conduction Abnormalities: Before initiating
therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct
preexisting electrolyte abnormalities, and consider discontinuing drugs known to
prolong QT interval. 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
Contraindications: TRISENOX is contraindicated in
patients who are hypersensitive to arsenic.
APL Differentiation Syndrome: Nine of 40 patients
with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation
Cardiac Conduction Abnormalities: Torsade de Pointes, Complete
Heart Block, and QT Prolongation: Sixteen of 40 patients (40%) had at
least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of
the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned
towards baseline by the end of 8 weeks after TRISENOX infusion. Monitor ECG weekly
and more frequently for clinically unstable patients. For QTc greater than 500 msec,
complete corrective measures and reassess the QTc with serial ECGs prior to initiating
TRISENOX. During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L
and magnesium concentrations above 1.8 mg/dL. Reassess patients who reach an absolute
QT interval value > 500 msec and immediately correct concomitant risk factors, if
any, while the risk/benefit of continuing versus suspending TRISENOX therapy should
be considered. The risk may be increased when TRISENOX is coadministered with medications
that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).
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. Advise pregnant women of the potential risk
to a fetus. Advise females and males of reproductive potential to use effective
contraception during and after treatment with TRISENOX.
Lactation: TRISENOX is excreted in human milk. Because
of the potential for serious adverse reactions in nursing infants, discontinue breastfeeding
during treatment with TRISENOX.
Laboratory Tests: Electrolyte and glucose levels,
as well as hepatic, renal, hematologic, and coagulation profiles should be monitored
at least twice weekly, and more frequently for clinically unstable patients during
the induction phase and at least weekly during the consolidation phase.
Drug Interactions: Avoid the concomitant use of TRISENOX
with medications that can prolong the QT/QTc interval or those that can lead to
electrolyte abnormalities. Concomitant use of drugs that can prolong the QT/QTc
interval with TRISENOX may increase the risk of serious QT/QTc interval prolongation.
Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation.
Monitor ECGs and electrolytes more frequently in patients who are unable to avoid
concomitant use of these medications and TRISENOX.
Pediatric Use: In a pediatric study, the toxicity
profile observed in 13 pediatric patients with APL between the ages of 4 and 20
receiving TRISENOX was similar to that observed in adult patients. Additional drug-related
toxicities reported included: gastrointestinal disorders, metabolic and nutrition
disorders, respiratory disorders, cardiac failure congestive, neuralgia, and enuresis.
One case each of pulmonary edema and caecitis were considered serious reactions.
No children less than 4 years of age were enrolled in the trial due to the rarity
of APL in this age group.
Patients with Renal Impairment: Exposure of arsenic
trioxide may be higher in patients with severe renal impairment. Patients with severe
renal impairment (creatinine clearance less than 30 mL/min) should be monitored
for toxicity when these patients are treated with TRISENOX, and 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) who are treated with TRISENOX for toxicity.
Most Common Adverse Reactions: Most patients experienced
some drug related toxicity, most commonly leukocytosis, gastrointestinal (nausea,
vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea,
cough, rash or itching, headaches, and dizziness. These adverse effects have not
been observed to be permanent or irreversible nor do they usually require interruption