Arsenic Trioxide

Approved Indications:

• Acute Promyelocytic Leukemia (APL):
• Newly Diagnosed APL: In combination with all-trans retinoic acid (ATRA) for patients with low- to intermediate-risk acute promyelocytic leukemia with t(15;17) translocation and/or PML-RARα gene expression.
• Relapsed or Refractory APL: As monotherapy in patients with APL who are resistant to, or have relapsed following, retinoid and anthracycline chemotherapy.

Off-label/Clinically Accepted Uses:

• Other hematologic malignancies (investigational and limited evidence): including multiple myeloma, myelodysplastic syndromes (MDS), and chronic myelogenous leukemia (CML).
• Solid tumors (under clinical investigation): melanoma, hepatocellular carcinoma, and esophageal cancer.

Route of Administration: Intravenous (IV) infusion only.

Adults:

• Relapsed/Refractory APL:
• Induction: 0.15 mg/kg IV once daily until bone marrow remission or for a maximum of 60 doses.
• Consolidation: 0.15 mg/kg IV once daily for 5 days/week for 4 weeks; repeat every 8 weeks for a total of 4 cycles.
• Newly Diagnosed APL (in combination with ATRA):
• Induction: 0.15 mg/kg IV once daily until bone marrow remission or for up to 60 doses.
• Consolidation: Administered in combination with ATRA in cycles; specific dosing varies per protocol.

Pediatrics:

• Limited but increasing data in children; doses generally extrapolated based on weight (mg/kg) and adult regimens, under specialist supervision.

Elderly:

• No specific adjustment required; monitor closely for cardiac and hepatic toxicity.

Hepatic Impairment:

• Use with caution; adjust or withhold dose if significant hepatotoxicity occurs.

Renal Impairment:

• Use with caution; no formal guidelines for adjustment, but increased monitoring is advised.

Administration Instructions:

• Infuse over 1–2 hours; dilute in 100–250 mL of 5% dextrose or normal saline before administration.
• Do not administer as a bolus.

Arsenic trioxide exerts antineoplastic effects by promoting apoptosis and differentiation in malignant cells, particularly in APL. It targets the PML-RARα fusion protein, causing its degradation, which allows the leukemic promyelocytes to undergo terminal differentiation and apoptosis. Additionally, arsenic trioxide generates reactive oxygen species (ROS) and induces mitochondrial damage, leading to cell cycle arrest and programmed cell death in leukemic cells. Its selective effect on APL cells makes it highly effective in targeting the molecular basis of the disease.

• Absorption: Not orally available; administered IV.
• Distribution: Rapid distribution phase; extensively distributed in body tissues, including liver, kidney, and heart.
• Protein Binding: 75–80%, mainly to albumin.
• Metabolism: Undergoes hepatic methylation to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA).
• Half-life:
• α-phase: ~1–2 hours
• β-phase: ~10–40 hours
• Excretion: Primarily via urine (60–70% within the first week), mostly as DMA and MMA.
• Steady-State Concentration: Reached by Day 8–10 with daily dosing.

• Pregnancy Category: Category D (Positive evidence of human fetal risk).
• Use only if potential benefit justifies risk to the fetus.
• Teratogenic and embryotoxic effects observed in animal studies.
• Lactation:
• Unknown if excreted in human milk.
• Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose due to potential infant toxicity.
• Recommendation: Use effective contraception during and for 6 months after treatment (females) and 3 months for males.

• Primary Class: Antineoplastic Agent
• Subclass: Differentiating Agent; Trivalent Arsenical

• Known hypersensitivity to arsenic trioxide or any component of the formulation
• QT prolongation at baseline (uncorrected)
• Congenital long QT syndrome
• Uncorrected electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia)

• QT Prolongation & Torsades de Pointes:
• Risk of life-threatening arrhythmias; ECG monitoring is essential.
• Differentiation Syndrome:
• May occur within days to weeks of treatment; potentially fatal.
• Symptoms: dyspnea, fever, weight gain, pulmonary infiltrates, pleural/pericardial effusion.
• Treat promptly with corticosteroids.
• Electrolyte Imbalance:
• Maintain normal serum potassium and magnesium levels throughout treatment.
• Hepatotoxicity:
• Monitor liver enzymes; withhold or reduce dose if significant elevation occurs.
• Renal Impairment:
• Accumulation possible; monitor renal function.
• Leukocytosis:
• Monitor CBC closely during induction.

Common Adverse Effects:

• Hematologic: Leukocytosis, anemia, thrombocytopenia
• Cardiac: QT prolongation, palpitations, arrhythmias
• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
• General: Fatigue, fever, edema, weight gain
• Hepatic: Elevated liver enzymes (AST, ALT), bilirubin

Serious Adverse Effects:

• Differentiation syndrome
• Torsades de pointes and sudden cardiac death
• Multiorgan failure
• Severe electrolyte imbalances

Rare/Delayed Effects:

• Peripheral neuropathy
• Myelosuppression
• Hepatic failure (rare)

• QT-Prolonging Drugs (e.g., amiodarone, fluoroquinolones, macrolides):
• Increased risk of torsades de pointes.
• CYP450 Involvement: Minimal hepatic enzyme interaction, but caution still warranted with potent inducers/inhibitors.
• Electrolyte-Depleting Drugs (e.g., diuretics):
• May potentiate hypokalemia/hypomagnesemia.
• Antineoplastic Agents:
• Synergistic toxicity risk when used with other cytotoxics.

Food/Alcohol Interactions:

• No significant food interactions.
• Alcohol should be avoided due to potential hepatotoxicity.

• FDA & EMA: Continued endorsement of arsenic trioxide in first-line APL therapy (in combination with ATRA), improving long-term remission rates.
• NCCN Guidelines: Arsenic trioxide + ATRA now considered standard of care for low- to intermediate-risk APL.
• Black Box Warning: Retained for QT prolongation and differentiation syndrome.
• Ongoing Trials: Being evaluated in combination regimens for relapsed hematologic malignancies and solid tumors.

• Temperature: Store vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Light/Humidity: Protect from light; keep in original carton until use.
• Handling:
• Diluted solutions should be used immediately or stored for up to 24 hours at 2°C–8°C.
• Do not freeze.
• Reconstitution: Not required; provided as a ready-to-dilute solution.