ARSENIC TRIOXIDE — arsenic trioxide
Fresenius Kabi USA, LLC
WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKE’S
Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection have experienced differentiation syndrome, which may be life-threatening or fatal. Signs and symptoms may include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy, and multi-organ dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold Arsenic Trioxide Injection [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
Cardiac Conduction Abnormalities: Arsenic Trioxide Injection can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering Arsenic Trioxide Injection, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection to patients with a ventricular arrhythmia or prolonged QTc interval. Withhold Arsenic Trioxide Injection until resolution and resume at reduced dose for QTc prolongation [see Dosage and Administration (2.3), Warnings and Precautions (5.2)].
Encephalopathy: Serious encephalopathy, including Wernicke’s, has occurred with Arsenic Trioxide Injection. Wernicke’s is a neurologic emergency. Consider testing thiamine levels in patients at risk for thiamine deficiency. Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving Arsenic Trioxide Injection. If Wernicke’s encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Warnings and Precautions (5.3)].
Arsenic Trioxide Injection is indicated for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
A treatment course for patients with relapsed or refractory APL consists of 1 induction cycle and 1 consolidation cycle [see Clinical Studies (14.2)].
- For the induction cycle, the recommended dosage of Arsenic Trioxide Injection is 0.15 mg/kg/day intravenously daily until bone marrow remission or up to a maximum of 60 days.
- For the consolidation cycle, the recommended dosage of Arsenic Trioxide Injection is 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction cycle.
During induction, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly.
Table 2 shows the dosage modifications for adverse reactions due to Arsenic Trioxide Injection when used alone.
|Adverse Reaction||Dosage Modification|
|Differentiation syndrome, defined by the presence of 2 or more of the following: || |
|QTc (Framingham formula)Prolongation greater than 450 msec for men or greater than 460 msec for women[see Warnings and Precautions (5.2)]|| |
|Hepatotoxicity, defined by 1 or more of the following: || |
|Other severe or life-threatening (grade 3-4) nonhematologic reactions[see Adverse Reactions (6)]|| |
|Moderate (grade 2) nonhematologic reactions[see Adverse Reactions (6)]|| |
|Leukocytosis (WBC count greater than 10 Gi/L)[see Adverse Reactions (6.1)]|| |
|Myelosuppression, defined by 1 or more of the following: || |
|Dose Level||Arsenic Trioxide Injection mg/kg intravenously once daily|
Dilute Arsenic Trioxide Injection with 100 to 250 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, using proper aseptic technique, immediately after withdrawal from the vial. Do not save any unused portions for later administration.
After dilution, store Arsenic Trioxide Injection for no more than 24 hours at room temperature and 48 hours when refrigerated.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Administer Arsenic Trioxide Injection as an intravenous infusion over 2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.
The Arsenic Trioxide Injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly. Do not mix Arsenic Trioxide Injection with other medications.
Safe Handling Procedures
Arsenic Trioxide Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1
Injection: 10 mg arsenic trioxide in 10 mL clear solution in a single-dose vial
Arsenic Trioxide Injection is contraindicated in patients with hypersensitivity to arsenic.
Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection. In clinical trials, 23% of patients treated with Arsenic Trioxide Injection 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.
If differentiation syndrome is suspected, temporarily withhold Arsenic Trioxide Injection 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)].
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