TRISENOX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRISENOX (TRISENOX).
Arsenic trioxide induces apoptosis in acute promyelocytic leukemia (APL) cells by targeting the PML-RARα fusion protein, leading to its degradation and subsequent differentiation and apoptosis. It also generates reactive oxygen species, disrupts mitochondrial function, and activates caspases.
| Metabolism | Arsenic trioxide undergoes hepatic methylation via arsenic(III) methyltransferase (AS3MT) to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). It is also converted to less toxic pentavalent forms. Excretion is primarily renal. |
| Excretion | Primarily renal excretion of unchanged arsenic (approximately 15-30% of the dose within 24 hours) with the remainder undergoing hepatic methylation to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are excreted renally. Biliary and fecal elimination are minor (<5%). |
| Half-life | Terminal elimination half-life for inorganic arsenic is approximately 10-14 hours, with a mean of 12 hours. The methylated metabolites have longer half-lives, contributing to accumulation with repeated dosing. Clinical context: Supports daily dosing schedule with monitoring for toxicity. |
| Protein binding | Arsenic trioxide is 95-99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 10-20 L/kg, indicating extensive tissue distribution, particularly to the liver, kidney, and skin. Clinical meaning: High Vd supports drug accumulation in tissues and prolonged elimination. |
| Bioavailability | Not applicable for oral route; only intravenous administration is approved. Bioavailability of oral formulation is approximately 85-90% but is not clinically used due to variable absorption and gastrointestinal toxicity. |
| Onset of Action | For intravenous administration (0.15 mg/kg/day): clinical response (e.g., reduction in peripheral blasts) may be observed within 7-14 days of treatment initiation. |
| Duration of Action | Duration of remission is variable; maintenance therapy may be required. Single course typically lasts 25-30 days with a 2-4 week rest period. Clinical notes: QTc prolongation can occur during treatment and may persist for several weeks after discontinuation. |
| Molecular Weight | 197.84 |
0.15 mg/kg IV daily until bone marrow remission, then 0.15 mg/kg IV 5 days/week for 2 weeks with 2 weeks off for up to 6 cycles.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment recommended for GFR ≥ 30 mL/min. For GFR < 30 mL/min, use with caution; no specific guidelines. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: avoid use. |
| Pediatric use | Safety and effectiveness in children <5 years not established. For children ≥5 years, 0.15 mg/kg IV using same schedule as adults. |
| Geriatric use | No specific dose adjustment; use same dosing as younger adults due to similar exposure, monitor renal function closely. |
| 1st trimester | Contraindicated due to teratogenicity; causes fetal harm based on animal studies and its mechanism as an antileukemic agent. |
| 2nd trimester | Contraindicated; risk of fetal malformations and developmental toxicity. |
| 3rd trimester | Contraindicated; potential fetal toxicity and bleeding risk due to thrombocytopenia. |
Clinical note
Comprehensive clinical and safety monograph for TRISENOX (TRISENOX).
| Placental transfer | Arsenic trioxide crosses the placenta; based on its low molecular weight and animal studies showing fetal distribution. |
| Breastfeeding | No data on presence in human milk; due to potential serious adverse reactions in nursing infants (e.g., leukopenia, thrombocytopenia), advise against breastfeeding during therapy and for at least 2 weeks after last dose. |
■ FDA Black Box Warning
WARNING: APL DIFFERENTIATION SYNDROME. Arsenic trioxide can cause a syndrome of fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, similar to retinoic acid syndrome. High-dose steroids should be initiated immediately if suspected.
| Serious Effects |
Hypersensitivity to arsenic trioxide or any excipientsPregnancy (teratogenic)
| Precautions | APL differentiation syndrome: May be life-threatening; treat with high-dose steroids at first suspicion., QT interval prolongation: Risk of torsade de pointes; monitor electrolytes and ECG; avoid other QT-prolonging drugs., Cardiac toxicity: Can cause atrioventricular block and ventricular arrhythmias; monitor cardiac function., Hepatotoxicity: Can cause elevated liver enzymes; monitor liver function tests., Electrolyte disturbances: Hypokalemia, hypomagnesemia, and hyperglycemia; correct before and during therapy., Neurotoxicity: Peripheral neuropathy, encephalopathy; discontinue if severe., Carcinogenicity: Arsenic is a known human carcinogen. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase arsenic levels. No other significant food interactions known. Maintain adequate hydration and electrolyte balance. |
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| Lactation Rating |
| L5 |
| Teratogenic Risk | TRISENOX (arsenic trioxide) is embryotoxic and teratogenic in animals. In humans, first trimester exposure carries high risk of spontaneous abortion and congenital malformations (neural tube defects, cardiac anomalies). Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and perinatal death. |
| Fetal Monitoring | Monitor complete blood count, electrolytes, renal and hepatic function, ECG (QTc interval) weekly. During pregnancy, obtain serial fetal ultrasound for growth and amniotic fluid volume, plus fetal echocardiogram. |
| Fertility Effects | Arsenic trioxide may impair fertility in both males and females based on animal studies. In humans, reversible amenorrhea and spermatogenesis suppression have been reported. |
| Clinical Pearls | Monitor ECG for QTc prolongation; maintain electrolytes (K+ >4 mEq/L, Mg2+ >1.8 mg/dL). Do not co-administer with other QTc-prolonging drugs. Premedicate for APL differentiation syndrome with corticosteroids. Use a dedicated IV line; do not mix with other medications. |
| Patient Advice | You will need regular blood tests to check your heart and electrolyte levels. · Report symptoms like irregular heartbeat, dizziness, or fainting immediately. · Avoid grapefruit and grapefruit juice during treatment. · You may experience fever, shortness of breath, or weight gain—seek medical attention. · Do not become pregnant during treatment; use effective contraception. · Do not breastfeed while taking this medication. |