Patients treated with Arsenic Trioxide Injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trial of patients with relapsed or refractory APL treated with Arsenic Trioxide Injection 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 Arsenic Trioxide Injection infusion, and it usually resolved by 8 weeks after Arsenic Trioxide Injection infusion. There are no data on the effect of Arsenic Trioxide Injection 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 Arsenic Trioxide Injection 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 Arsenic Trioxide Injection, assess the QTc interval by electrocardiogram, correct pre-existing 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. 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 Arsenic Trioxide Injection 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 Arsenic Trioxide Injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume Arsenic Trioxide Injection at a reduced dose [see Dosage and Administration (2.3)].
Serious encephalopathies were reported in patients receiving Arsenic Trioxide Injection. 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 occurred in patients receiving Arsenic Trioxide Injection. 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 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.
Long-term liver abnormalities can occur in patients with APL treated with Arsenic Trioxide Injection.
During treatment with Arsenic Trioxide Injection, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection 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)].
The active ingredient of Arsenic Trioxide Injection, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.
Arsenic Trioxide Injection 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/m² 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/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Differentiation Syndrome [see Warnings and Precautions (5.1)]
- Cardiac Conduction Abnormalities [see Warnings and Precautions (5.2)]
- Encephalopathy [see Warnings and Precautions (5.3)]
- Hepatotoxicity [see Warnings and Precautions (5.4)]
- Carcinogenesis [see Warnings and Precautions (5.5)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Relapsed or Refractory APL
Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of Arsenic Trioxide Injection. Forty patients in the Study PLRXAS01 received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose.
Serious adverse reactions observed in the 40 patients with refractory or relapsed APL enrolled in Study PLRXAS01 included differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2).
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.
Table 5 describes the adverse reactions in patients aged 5 to 73 years with APL who received Arsenic Trioxide Injection at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received Arsenic Trioxide Injection.
|Body System Adverse reaction||Any GradeAdverse Reactions||Grade ≥3Adverse Reactions|
|Abdominal pain (lower & upper)||23||58||4||10|
|Post nasal drip||5||13|
|Decreased breath sounds||4||10|
|General disorders and administration site conditions|
|Edema — non-specific||16||40|
|Injection site pain||8||20|
|Pain — non-specific||6||15||1||3|
|Injection site erythema||5||13|
|Injection site edema||4||10|
|Nervous system disorders|
|Dizziness (excluding vertigo)||9||23|
|ECG QT corrected interval prolonged > 500 msec||16||40|
|ECG abnormal other than QT interval prolongation||3||8|
|Metabolism and nutrition disorders|
|Body System Adverse reaction||Any GradeAdverse Reactions||Grade ≥3Adverse Reactions|
|Disseminated intravascular coagulation||3||8||3||8|
|Skin and subcutaneous tissue disorders|
|Erythema — non-specific||5||13|
|Non-specific skin lesions||3||8|
|Musculoskeletal, connective tissue, and bone disorders|
|Pain in limb||5||13||2||5|
|Infections and infestations|
|Upper respiratory tract infection||5||13||1||3|
|Bacterial infection — non-specific||3||8||1||3|
|Reproductive system disorders|
|Painful red eye||2||5|
|Renal and urinary disorders|
Other Clinically Relevant Adverse Reactions
Arsenic Trioxide Injection can induce proliferation of leukemic promyelocytes resulting in a rapid increased in white blood cell count. Leukocytosis greater than 10 Gi/L developed during induction therapy in 50% of patients receiving Arsenic Trioxide Injection monotherapy for relapsed/refractory APL. A relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts.
RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.