The following serious adverse reactions have been associated with TRISENOX in clinical trials and are discussed in greater detail in other sections of the label.
- APL Differentiation Syndrome [see WARNINGS AND PRECAUTIONS]
- Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, and QT Prolongation [see WARNINGS AND PRECAUTIONS]
- Carcinogenesis [see WARNINGS AND PRECAUTIONS]
- Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
- Laboratory Tests [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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.
Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of TRISENOX. Forty patients in the Phase 2 study received the recommended dose of 0.15 mg/kg of which 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. 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 of therapy.
Serious adverse events (SAEs), Grade 3/4 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to TRISENOX in the Phase 2 study of 40 patients with refractory or relapsed APL included APL 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).
Table 1 describes the adverse events that were observed in patients, between the ages of 5-73 years, treated for APL with TRISENOX at the recommended dose at a rate of 5% or more. Similar adverse event profiles were seen in the other patient populations who received TRISENOX.
Table 1 : Adverse Events (Any Grade) Occurring in ≥ 5% of 40 Patients with APL Who Received TRISENOX (arsenic trioxide) Injection at a Dose of 0.15 mg/kg/day
|System organ class Adverse event||All Adverse Events, Any Grade||Grade 3/4 Events|
|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|
|Abdominal pain (lower & upper)||23||58||4||10|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Dizziness (excluding vertigo)||9||23|
|Post nasal drip||5||13|
|Decreased breath sounds||4||10|
|Skin & subcutaneous tissue disorders|
|Erythema - non-specific||5||13|
|Non-specific skin lesions||3||8|
|ECG QT corrected interval prolonged > 500 msec||16||40|
|ECG abnormal other than QT interval prolongation||3||8|
|Infections and infestations|
|Upper respiratory tract infection||5||13||1||3|
|Bacterial infection - non-specific||3||8||1||3|
|Musculoskeletal, connective tissue and bone disorders|
|Pain in limb||5||13||2||5|
|Disseminated intravascular coagulation||3||8||3||8|
|Painful red eye||2||5|
|Renal and urinary disorders|
|Reproductive system disorders|
The following additional adverse events were reported as related to TRISENOX treatment in 13 pediatric patients (defined as ages 4 through 20): gastrointestinal (dysphagia, mucosal inflammation/stomatitis, oropharyngeal pain, caecitis), metabolic and nutrition disorders (hyponatremia, hypoalbuminemia, hypophosphatemia, and lipase increased), cardiac failure congestive, respiratory (acute respiratory distress syndrome, lung infiltration, pneumonitis, pulmonary edema, respiratory distress, capillary leak syndrome), neuralgia, and enuresis. Pulmonary edema (n=1) and caecitis (n=1) were considered serious reactions.
The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Cardiac disorders: ventricular extrasystoles in association with QT prolongation, and ventricular tachycardia in association with QT prolongation.
Nervous system disorders: peripheral neuropathy
Hematologic disorders: pancytopenia
Investigations: gamma-glutamyltransferase increased
Respiratory, thoracic, and mediastinal disorders: A differentiation syndrome, like retinoic acid syndrome, has been reported with the use of TRISENOX for the treatment of malignancies other than APL [see BOXED WARNING].