Usage
Arsenic Trioxide is indicated for the induction of remission and consolidation in adult patients with:
- Newly diagnosed low-to-intermediate risk acute promyelocytic leukemia (APL) (white blood cell count ≤ 10 x 10³/µl) in combination with all-trans-retinoic acid (ATRA).
- Relapsed/refractory acute promyelocytic leukemia (APL) (previous treatment should have included a retinoid and chemotherapy) characterized by the presence of the t(15;17) translocation and/or the presence of the promyelocytic leukemia/retinoic-acid-receptor-alpha (PML/RAR-alpha) gene.
Pharmacological Classification: Antineoplastic agent.
Mechanism of Action: Arsenic Trioxide induces apoptosis (programmed cell death) in APL cells by promoting differentiation of promyelocytes and degradation of the PML/RAR-alpha fusion protein.
Alternate Names
- Arsenious acid
- Trisenox (brand name)
How It Works
Pharmacodynamics: Arsenic Trioxide primarily targets leukemic promyelocytes, leading to their differentiation and apoptosis. It disrupts the PML/RAR-alpha fusion protein, crucial for APL development.
Pharmacokinetics:
- Absorption: Administered intravenously, achieving rapid systemic distribution.
- Metabolism: Metabolized to arsenious acid (AsIII), the pharmacologically active form. Further methylation and oxidation can occur.
- Elimination: Primarily renal excretion of unchanged drug and metabolites.
Mode of Action: Binds to cysteine residues in the PML portion of the PML/RAR-alpha fusion protein, leading to its degradation and promoting differentiation and apoptosis of leukemic cells.
Receptor Binding/Enzyme Inhibition: Primarily targets the PML/RAR-alpha fusion protein.
Elimination Pathways: Predominantly renal excretion.
Dosage
Arsenic Trioxide must be administered intravenously, typically over 1-2 hours.
Standard Dosage
Adults:
- Induction: 0.15 mg/kg/day until complete remission (bone marrow < 5% blasts, no evidence of leukemic cells) or up to a maximum of 60 days.
- Consolidation: 0.15 mg/kg/day for 25 doses over 5 weeks (5 days on, 2 days off), starting 3-6 weeks after induction.
Children (4 years and older): Similar dosing to adults. Pediatric use requires careful monitoring.
Special Cases:
- Elderly Patients: Same dose as adults, with close monitoring.
- Patients with Renal Impairment: Use with caution. Dose reduction may be necessary if creatinine clearance < 30 mL/min. No data for dialysis patients.
- Patients with Hepatic Dysfunction: Use with caution, monitor for toxicity. Dosage adjustments may be warranted in severe hepatic impairment.
- Patients with Comorbid Conditions: Assess and manage comorbidities (e.g., cardiac disease, diabetes) appropriately.
Clinical Use Cases
Arsenic Trioxide’s clinical use is primarily focused on APL management and not typically employed in settings like intubation, surgical procedures, mechanical ventilation, or general ICU/emergency situations outside of APL-related complications.
Dosage Adjustments
Dosage adjustments are based on toxicity, including:
- Hematologic Toxicity: Dose reduction may be needed.
- Hepatotoxicity: Withhold if total bilirubin > 3 x ULN, AST/ALT > 5 x ULN, or alkaline phosphatase > 5 x ULN. Resume at a reduced dose (50%) after resolution.
- QTc Prolongation: Withhold Arsenic Trioxide and any QTc-prolonging medications. Correct electrolyte abnormalities. Resume at a reduced dose after normalization.
Side Effects
Common Side Effects:
- Leukopenia, thrombocytopenia, anemia
- Nausea, vomiting, diarrhea
- Fatigue, headache, dizziness
- Electrolyte imbalances (hypokalemia, hypomagnesemia)
- Elevated liver enzymes
- Rash
Rare but Serious Side Effects:
- QTc prolongation, arrhythmias (including Torsades de Pointes)
- Differentiation syndrome (fever, weight gain, pulmonary infiltrates, respiratory distress)
- Hepatotoxicity
- Encephalopathy (including Wernicke’s encephalopathy)
- Leukocytosis
Long-Term Effects: Secondary malignancies (potential).
Adverse Drug Reactions (ADR): Severe differentiation syndrome, serious cardiac arrhythmias, hepatotoxicity, severe encephalopathy.
Contraindications
- Hypersensitivity to arsenic.
Drug Interactions
- Drugs that prolong the QTc interval (e.g., antiarrhythmics, certain antibiotics).
- Medications metabolized by CYP450 enzymes.
- Monitor for interactions with concomitant medications.
Pregnancy and Breastfeeding
Arsenic Trioxide is contraindicated during pregnancy and breastfeeding due to potential teratogenic effects and unknown risks to the neonate.
Drug Profile Summary
- Mechanism of Action: Induces apoptosis and differentiation of APL cells, degrades PML-RARα fusion protein.
- Side Effects: Myelosuppression, gastrointestinal effects, QTc prolongation, differentiation syndrome, hepatotoxicity, encephalopathy.
- Contraindications: Hypersensitivity to arsenic, pregnancy, breastfeeding.
- Drug Interactions: QTc-prolonging drugs, CYP450 substrates.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 0.15 mg/kg/day IV; induction until remission (max 60 days), consolidation for 25 doses/5 weeks.
- Monitoring Parameters: Complete blood count, electrolytes, liver function tests, ECG (QTc interval).
Popular Combinations
- All-trans-retinoic acid (ATRA) for newly diagnosed APL.
Precautions
- General Precautions: Monitor for hematologic, hepatic, and cardiac toxicity. Baseline ECG and electrolyte assessment recommended.
- Specific Populations: Monitor closely in elderly patients and those with renal/hepatic impairment. Contraindicated in pregnancy and breastfeeding.
- Lifestyle Considerations: Patients should maintain adequate hydration.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Arsenic Trioxide?
A: 0.15 mg/kg/day intravenously. Induction continues until remission (up to 60 days), followed by consolidation (25 doses over 5 weeks).
Q2: What are the most serious side effects of Arsenic Trioxide?
A: QTc prolongation, potentially fatal arrhythmias, differentiation syndrome, hepatotoxicity, and encephalopathy are the most serious potential side effects.
Q3: How is Arsenic Trioxide administered?
A: Intravenously, typically over 1-2 hours, with adjustments up to 4 hours if vasomotor reactions occur.
Q4: What is differentiation syndrome, and how is it managed?
A: Differentiation syndrome is characterized by fever, weight gain, dyspnea, pulmonary infiltrates, and other symptoms. Management includes high-dose corticosteroids (e.g., dexamethasone), supportive care (oxygen, diuretics), and temporary cessation of Arsenic Trioxide if severe.
Q5: How should QTc prolongation be managed in patients receiving Arsenic Trioxide?
A: Discontinue Arsenic Trioxide and any other QTc-prolonging agents, correct electrolyte imbalances, and monitor ECG. Resume Arsenic Trioxide at a reduced dose after QTc normalization.
Q6: Is Arsenic Trioxide safe to use during pregnancy or breastfeeding?
A: No, it’s contraindicated due to potential fetal harm and unknown risks to infants.
Q7: What monitoring is essential during Arsenic Trioxide therapy?
A: Regular complete blood counts, electrolyte levels, liver function tests, and ECGs (for QTc interval) are crucial for monitoring potential toxicities.
Q8: What is the role of Arsenic Trioxide in combination with ATRA?
A: The combination of Arsenic Trioxide and ATRA is standard treatment for newly diagnosed low-to-intermediate risk APL, resulting in high remission rates.
Q9: Are there any specific precautions for patients with renal or hepatic impairment?
A: Arsenic Trioxide should be used cautiously in these patient populations, with close monitoring and potential dose adjustments based on creatinine clearance and liver function. No data supports its usage in dialysis patients.
Q10: What is the mechanism of action of Arsenic Trioxide in APL?
A: Arsenic trioxide targets the PML/RAR-alpha fusion protein, leading to its degradation. This induces differentiation and apoptosis of APL cells and promotes remission.
