ARSENIC TRIOXIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ARSENIC TRIOXIDE (ARSENIC TRIOXIDE).

How it works

Arsenic trioxide induces apoptosis in acute promyelocytic leukemia (APL) cells through degradation of PML-RARα fusion protein and modulation of mitochondrial pathways.

What the body does with it

Metabolism	Arsenic trioxide undergoes methylation in the liver via arsenic methyltransferase (AS3MT) to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA).
Excretion	Primarily renal excretion; after intravenous administration, approximately 15% of the dose is excreted unchanged in urine over 24 hours. Biliary/fecal excretion accounts for less than 5% as unchanged drug; the majority is eliminated as methylated metabolites (monomethylarsonic acid and dimethylarsinic acid) via urine, with total urinary excretion of arsenic species reaching 60-85% of the dose within 14 days.
Half-life	Terminal elimination half-life of inorganic arsenic is approximately 10–14 hours for the trivalent form, but for total arsenic (including methylated metabolites) the half-life ranges from 10 to 32 hours. Clinical context: due to extensive tissue distribution and metabolic conversion, the effective half-life for pharmacodynamic effect is prolonged, with repeated dosing leading to accumulation. The terminal half-life is biphasic: an initial distribution phase of about 2 hours and a terminal phase of 10–14 hours.
Protein binding	Approximately 75% bound to plasma proteins, primarily albumin and, to a lesser extent, α1-acid glycoprotein and globulins. Binding is saturable and concentration-dependent within the therapeutic range.
Volume of Distribution	Volume of distribution at steady state (Vd_ss) is approximately 3–6 L/kg, indicating extensive distribution into tissues, including liver, kidney, and bone marrow. The large Vd reflects binding to sulfhydryl groups in tissues and accumulation in hair, skin, and nails. Mean Vd ranges from 4.4 to 5.8 L/kg in adults.
Bioavailability	Oral bioavailability is approximately 80–100% in humans, but clinically relevant route is intravenous only due to gastrointestinal toxicity and unpredictable absorption. No subcutaneous or intramuscular formulations exist.
Onset of Action	Intravenous: Clinical effect (induction of remission in acute promyelocytic leukemia) is typically observed within 30–60 minutes after infusion for hemodynamic changes; antileukemic effect requires repeated dosing over days to weeks. No other routes of administration are clinically relevant.
Duration of Action	Intravenous: Antileukemic effect persists for the duration of treatment (typically 25–60 days per cycle). After discontinuation, the drug is cleared within weeks, but differentiation syndrome may occur up to 60 days after the last dose. Hemodynamic effects (QT prolongation) resolve within hours to days after stopping the infusion.

Classification & Brands

Dosing & administration

0.15 mg/kg IV daily until remission, then 0.15 mg/kg IV 5 days per week for 5 weeks (consolidation); dose based on actual body weight.

Dosage form	INJECTABLE
Renal impairment	No specific dose adjustment recommended for renal impairment; use with caution in severe renal impairment (CrCl <30 mL/min) due to potential toxicity.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce starting dose to 0.10 mg/kg IV daily; Child-Pugh C: avoid use or reduce to 0.07 mg/kg IV daily with close monitoring.
Pediatric use	0.15 mg/kg IV daily for induction (same as adults); maximum dose 10 mg/day; consolidation: 0.15 mg/kg IV 5 days per week for 5 weeks; safety not established for <5 years.
Geriatric use	No specific dose adjustment required; monitor renal function and electrolytes closely due to increased risk of QT prolongation and nephrotoxicity.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ARSENIC TRIOXIDE (ARSENIC TRIOXIDE).

Breastfeeding

Arsenic is excreted into breast milk. The milk-to-plasma ratio is unknown for arsenic trioxide specifically. Breastfeeding is not recommended during therapy due to potential for arsenic accumulation in the infant and associated neurotoxicity or carcinogenic risk. A washout period of at least 2 weeks after last dose is advised.

Teratogenic Risk

Arsenic trioxide is embryotoxic and teratogenic in animal studies. In humans, first trimester exposure may increase risk of congenital malformations (neural tube defects, cardiac anomalies) and spontaneous abortion. Second and third trimester exposure can cause fetal growth restriction, oligohydramnios, and fetal distress. Limited human data precludes precise risk quantification; contraindicated unless maternal benefit clearly outweighs fetal risk.

Warnings & precautions

■ FDA Black Box Warning

Risk of differentiation syndrome, cardiac arrhythmias (QT prolongation, torsade de pointes), and severe hepatotoxicity.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to arsenic or any component; history of torsade de pointes; pre-existing QT prolongation (QTc > 500 ms); severe hepatic impairment.

Clinical Precautions

Precautions	Monitor for differentiation syndrome, QT interval prolongation, electrolyte imbalances (potassium, magnesium), and liver function; avoid concurrent use of other QT-prolonging drugs.
Food/Dietary	Avoid grapefruit juice (may increase arsenic levels). Limit alcohol consumption. Maintain adequate hydration; no specific food restrictions other than avoiding grapefruit juice.

Clinical Tips & Counseling

Drug interactions

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ARSENIC TRIOXIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ARSENIC TRIOXIDE (ARSENIC TRIOXIDE).

How it works

Arsenic trioxide induces apoptosis in acute promyelocytic leukemia (APL) cells through degradation of PML-RARα fusion protein and modulation of mitochondrial pathways.

What the body does with it

Metabolism	Arsenic trioxide undergoes methylation in the liver via arsenic methyltransferase (AS3MT) to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA).
Excretion	Primarily renal excretion; after intravenous administration, approximately 15% of the dose is excreted unchanged in urine over 24 hours. Biliary/fecal excretion accounts for less than 5% as unchanged drug; the majority is eliminated as methylated metabolites (monomethylarsonic acid and dimethylarsinic acid) via urine, with total urinary excretion of arsenic species reaching 60-85% of the dose within 14 days.
Half-life	Terminal elimination half-life of inorganic arsenic is approximately 10–14 hours for the trivalent form, but for total arsenic (including methylated metabolites) the half-life ranges from 10 to 32 hours. Clinical context: due to extensive tissue distribution and metabolic conversion, the effective half-life for pharmacodynamic effect is prolonged, with repeated dosing leading to accumulation. The terminal half-life is biphasic: an initial distribution phase of about 2 hours and a terminal phase of 10–14 hours.
Protein binding	Approximately 75% bound to plasma proteins, primarily albumin and, to a lesser extent, α1-acid glycoprotein and globulins. Binding is saturable and concentration-dependent within the therapeutic range.
Volume of Distribution	Volume of distribution at steady state (Vd_ss) is approximately 3–6 L/kg, indicating extensive distribution into tissues, including liver, kidney, and bone marrow. The large Vd reflects binding to sulfhydryl groups in tissues and accumulation in hair, skin, and nails. Mean Vd ranges from 4.4 to 5.8 L/kg in adults.
Bioavailability	Oral bioavailability is approximately 80–100% in humans, but clinically relevant route is intravenous only due to gastrointestinal toxicity and unpredictable absorption. No subcutaneous or intramuscular formulations exist.
Onset of Action	Intravenous: Clinical effect (induction of remission in acute promyelocytic leukemia) is typically observed within 30–60 minutes after infusion for hemodynamic changes; antileukemic effect requires repeated dosing over days to weeks. No other routes of administration are clinically relevant.
Duration of Action	Intravenous: Antileukemic effect persists for the duration of treatment (typically 25–60 days per cycle). After discontinuation, the drug is cleared within weeks, but differentiation syndrome may occur up to 60 days after the last dose. Hemodynamic effects (QT prolongation) resolve within hours to days after stopping the infusion.

Classification & Brands

Dosing & administration

0.15 mg/kg IV daily until remission, then 0.15 mg/kg IV 5 days per week for 5 weeks (consolidation); dose based on actual body weight.

Dosage form	INJECTABLE
Renal impairment	No specific dose adjustment recommended for renal impairment; use with caution in severe renal impairment (CrCl <30 mL/min) due to potential toxicity.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce starting dose to 0.10 mg/kg IV daily; Child-Pugh C: avoid use or reduce to 0.07 mg/kg IV daily with close monitoring.
Pediatric use	0.15 mg/kg IV daily for induction (same as adults); maximum dose 10 mg/day; consolidation: 0.15 mg/kg IV 5 days per week for 5 weeks; safety not established for <5 years.
Geriatric use	No specific dose adjustment required; monitor renal function and electrolytes closely due to increased risk of QT prolongation and nephrotoxicity.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ARSENIC TRIOXIDE (ARSENIC TRIOXIDE).

Breastfeeding

Teratogenic Risk

Warnings & precautions

■ FDA Black Box Warning

Risk of differentiation syndrome, cardiac arrhythmias (QT prolongation, torsade de pointes), and severe hepatotoxicity.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to arsenic or any component; history of torsade de pointes; pre-existing QT prolongation (QTc > 500 ms); severe hepatic impairment.

Clinical Precautions

Precautions	Monitor for differentiation syndrome, QT interval prolongation, electrolyte imbalances (potassium, magnesium), and liver function; avoid concurrent use of other QT-prolonging drugs.
Food/Dietary	Avoid grapefruit juice (may increase arsenic levels). Limit alcohol consumption. Maintain adequate hydration; no specific food restrictions other than avoiding grapefruit juice.

Clinical Tips & Counseling

Drug interactions

Loading safety data…