Arsenic trioxide, a proapoptotic agent, is an antineoplastic agent.1, 9
Arsenic trioxide is used in combination with tretinoin for the treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or promyelocytic leukemia retinoic acid receptor alpha (PML-RARα) gene expression.1 Arsenic trioxide is also used for induction of remission and consolidation in patients with APL characterized by the t(15;17) chromosomal translocation or expression of the PML-RARα fusion gene whose disease is refractory to, or has relapsed after retinoid- and anthracycline-based chemotherapy.1 Arsenic trioxide has been designated an orphan drug by FDA for the treatment of APL.11
Initial Treatment for Newly Diagnosed Low-Risk Disease
Efficacy of arsenic trioxide in combination with tretinoin for initial treatment of low-risk APL is based on results from a multicenter, randomized, open-label trial in 162 adults with newly diagnosed disease presenting with a white blood cell count (WBC) ≤10 gibicells per liter (Gi/L).1, 2, 3 Patients were randomized to receive arsenic trioxide plus tretinoin for induction and consolidation or chemotherapy plus tretinoin for induction, consolidation, and maintenance.1, 3 In the arsenic trioxide/tretinoin arm, induction therapy consisted of arsenic trioxide 0.15 mg/kg IV once daily plus tretinoin 22.5 mg/m2 orally twice daily until hematologic complete remission or for up to 60 days.1 Patients who achieved complete remission then received 4 consolidation cycles of 8 weeks each, with arsenic trioxide 0.15 mg/kg IV once daily for 5 days every week during weeks 1 through 4 of each cycle, in combination with tretinoin 22.5 mg/m2 orally twice daily during weeks 1‒2 and 5‒6; tretinoin was omitted during weeks 5‒6 of the last cycle.1 In the chemotherapy/tretinoin arm, induction therapy consisted of idarubicin 12 mg/m2 IV once daily on days 2, 4, 6, and 8 plus tretinoin 22.5 mg/m2 orally twice daily starting on day 1 until hematologic complete remission or for up to 60 days.1 Patients in the chemotherapy/tretinoin group who achieved complete remission then received consolidation and maintenance therapy with tretinoin in combination with chemotherapy.1
Efficacy was assessed by the 2-year event-free survival (EFS) rate, defined as the time from randomization to treatment failure, including failure to achieve hematologic complete remission or complete remission with incomplete hematologic recovery after induction therapy, failure to achieve molecular remission after 3 consolidation courses, molecular relapse, hematologic relapse, or death.1 The primary analysis compared the proportion of patients achieving EFS at 2 years between treatment arms.1 After a median follow-up of 34.4 months, the 2-year EFS rate in the modified intent-to-treat population (patients who received at least 1 assigned dose) was significantly improved in patients who received arsenic trioxide/tretinoin (94%) compared with those who received chemotherapy/tretinoin (82%).1 The 2-year overall survival rate in the modified intent-to-treat population was not significantly different between the treatment groups (99% with arsenic trioxide/tretinoin and 91% with chemotherapy/tretinoin).1
Treatment for Relapsed or Refractory Disease
Efficacy of arsenic trioxide in patients with relapsed or refractory APL is based on results from an open-label, single-arm, phase 2 trial in 40 patients who were previously treated with anthracycline- and retinoid-based therapy.1 Arsenic trioxide 0.15 mg/kg IV was administered daily over 1-2 hours until bone marrow clearance of leukemic cells or for a maximum of 60 days.1 Complete response, defined as absence of visible leukemic cells in the bone marrow with recovery of platelet and WBC count and confirmatory bone marrow evaluation at least 30 days later, occurred in 28 patients (70%).1 The median time to bone marrow remission was 44 days, and median time to onset of complete response was 53 days.1 The complete response rate was 82% in the 22 patients who relapsed within 1 year after tretinoin therapy and 55% in the 18 patients who received arsenic trioxide ≥1 year after tretinoin therapy.1 Following 3‒6 weeks of remission, 31 patients received consolidation therapy with the same daily dosage of arsenic trioxide for 25 additional days over a period of up to 5 weeks.1 During follow-up, 18 patients received maintenance arsenic trioxide and 15 underwent bone marrow transplantation.1 At last follow-up, 27 of 40 patients were alive with a median follow-up of 484 days, and 23 of 40 patients remained in complete response with a median follow-up of 483 days.1 Among the 28 patients who met response criteria, cytogenetic conversion to no detection of the APL chromosome rearrangement occurred in 24 patients (86%), and reverse transcription polymerase chain reaction (RT-PCR) conversion to no detection of the APL gene rearrangement occurred in 22 patients (79%).1
Efficacy of arsenic trioxide in pediatric patients with relapsed or refractory APL is based on results of the phase 2 study in 40 patients with relapsed or refractory APL.1 The study included 5 pediatric patients (5 to 16 years of age) who were treated with arsenic trioxide at the recommended dosage of 0.15 mg/kg/day.1
The treatment of APL has evolved rapidly over the past several decades with the introduction of tretinoin and arsenic trioxide.8 APL is a distinct subtype of acute myeloid leukemia (AML) that has a specific sensitivity to tretinoin, which acts as a differentiating agent, and to arsenic trioxide, a proapoptotic agent; high complete recovery rates and long-term disease-free survival in APL have been demonstrated with the combination of the 2 drugs.9, 10 With the inclusion of arsenic trioxide in current treatment regimens, the use of traditional chemotherapy is increasingly restricted to the induction phase for high-risk patients.10 Current guidelines for APL include various treatment options; selection of an appropriate regimen is determined by the patient's risk category (low, intermediate, or high based on WBC counts).8
Experts currently recommend the use of arsenic trioxide in combination with tretinoin for initial treatment of APL in patients with low- to intermediate-risk disease (WBC count ≤10,000/mm3).8, 9, 10 In such patients, arsenic trioxide in combination with tretinoin therapy may be used without conventional cytotoxic chemotherapy.6, 7, 8, 9 For patients who are treated with arsenic trioxide and tretinoin and achieve remission, maintenance therapy is generally not required.8 Arsenic trioxide, often in combination with tretinoin, is considered the treatment of choice in patients with relapsed or refractory APL to achieve a second molecular remission.7
Dispensing and Administration Precautions
Administer arsenic trioxide by IV infusion.1 Arsenic trioxide is commercially available as a 1 mg/mL and 2 mg/mL injection that is further diluted prior to administration.1, 5, 12
Unopened vials of arsenic trioxide should be stored at 20‒25°C; excursions permitted to 15‒30°C.1 Do not freeze.1
Dilute appropriate dose in 100‒250 mL of 5% dextrose injection or 0.9% sodium chloride; discard any unused portion.1
Store the diluted solution for ≤24 hours at room temperature or ≤48 hours under refrigeration.1
Administer by IV infusion over 2 hours; if acute vasomotor reactions occur, may extend infusion to up to 4 hours.1 Administration via a central venous catheter is not required.1 Do not mix arsenic trioxide with other medications.1
Newly-Diagnosed Low-Risk Acute Promyelocytic Leukemia
A treatment course for adults with newly-diagnosed low-risk APL consists of 1 induction cycle followed by 4 consolidation cycles.1
For the induction cycle, the recommended dosage of arsenic trioxide is 0.15 mg/kg IV once daily in combination with tretinoin 22.5 mg/m2 (rounded to the nearest 10 mg) orally twice daily until bone marrow remission, up to a maximum of 60 days.1
For the consolidation cycle, the recommended dosage of arsenic trioxide is 0.15 mg/kg IV once daily on days 1‒5 each week during weeks 1‒4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin.1 Administer tretinoin 22.5 mg/m2 (rounded to the nearest 10 mg) orally twice daily on days 1‒7 during weeks 1 and 2 and weeks 5 and 6; omit tretinoin during weeks 5 and 6 of the fourth consolidation cycle.1
Relapsed or Refractory Acute Promyelocytic Leukemia
A treatment course consists of 1 induction cycle and 1 consolidation cycle.1
For the induction cycle, the recommended dosage of arsenic trioxide is 0.15 mg/kg IV daily until bone marrow remission or for up to a maximum of 60 days.1
For the consolidation cycle, the recommended dosage of arsenic trioxide is 0.15 mg/kg IV daily for 25 doses over a period of up to 5 weeks.1 Begin consolidation 3‒6 weeks after induction.1
Dosage Modification for Toxicity
Dose Level | Arsenic trioxide | Tretinoin (rounded to the nearest 10 mg) |
|---|---|---|
Starting Dose | 0.15 mg/kg IV once daily | 22.5 mg/m2orally twice daily |
First Dose Reduction | 0.11 mg/kg IV once daily | 18.75 mg/m2orally twice daily |
Second Dose Reduction | 0.10 mg/kg IV once daily | 12.5 mg/m2orally twice daily |
Third Dose Reduction | 0.075 mg/kg IV once daily | 10 mg/m2orally twice daily |
If differentiation syndrome occurs (defined by ≥2 of the following: unexplained fever, dyspnea, pleural or pericardial effusion, pulmonary infiltrates, renal failure, hypotension, or weight gain >5 kg), temporarily withhold arsenic trioxide and consider withholding tretinoin if symptoms are severe.1
Administer dexamethasone 10 mg IV every 12 hours for at least 3 days; continue until signs and symptoms resolve.1
When the patient improves, resume treatment and reduce dose of the withheld drug(s) by 50%.1 Increase the dose of the withheld drug or drugs to the recommended dose after 1 week if symptoms do not recur; if symptoms recur, reduce arsenic trioxide and/or tretinoin to the previous dosage.1
For QTcinterval >450 milliseconds in men or >460 milliseconds in women, withhold arsenic trioxide and any concomitant medication known to prolong the QTc interval.1 Correct electrolyte abnormalities.1
After the QTc interval normalizes and electrolytes are corrected, resume arsenic trioxide at 50% of the usual dose (0.075 mg/kg/day) for 1 week.1 If the 50% reduced dosage is tolerated without recurrent QTc prolongation, increase the dosage of arsenic trioxide to 0.11 mg/kg daily for the next week.1 The dose of arsenic trioxide can be increased to 0.15 mg/kg daily if QTcprolongation does not recur during the 2-week dose-escalation period.1
If hepatotoxicity occurs (defined by 1 or more of the following: total bilirubin >3 times the upper limit of normal [ULN], AST >5 times the ULN, or alkaline phosphatase [AP] >5 times the ULN), withhold arsenic trioxide and/or tretinoin.1 When total bilirubin decreases to <1.5 times the ULN and AP/AST decrease to <3 times the ULN, resume the withheld drug or drugs at 50% of the usual dose.1 After 1 week without worsening hepatotoxicity, increase the dose of the withheld drug(s) back to the recommended dose; permanently discontinue the withheld drug or drugs if hepatotoxicity recurs.1
Other Severe or Life-Threatening Nonhematologic Reactions
If other severe or life-threatening nonhematologic reactions occur, temporarily withhold arsenic trioxide and tretinoin.1 When the reaction resolves to grade 1 or lower, resume arsenic trioxide and tretinoin reduced by 2 dose levels (see Table 1).1
Moderate Nonhematologic Reactions
If a moderate (grade 2) nonhematologic reaction occurs, reduce the dose of arsenic trioxide and/or tretinoin by 1 dose level (see Table 1).1
If leukocytosis occurs (defined as WBC count >10 gibicells per liter [Gi/L]), administer hydroxyurea and discontinue hydroxyurea when WBC count decreases to <10 Gi/L.1
If myelosuppression occurs (defined as an absolute neutrophil count <1 Gi/L or a platelet count <50 Gi/L persisting for more than 5 weeks), consider reducing arsenic trioxide and tretinoin by 1 dose level (see Table 1).1
If myelosuppression lasts ≥50 days or occurs during 2 consecutive cycles, assess bone marrow aspirate for remission status; if molecular remission is present, resume arsenic trioxide and tretinoin at 1 dose level lower.1
The manufacturer makes no specific dosage recommendations in patients with hepatic impairment; however, caution is advised.1 Dosage adjustment is needed for treatment-related hepatic impairment.1 Monitor patients with severe hepatic impairment (Child-Pugh Class C) frequently for toxicity.1
Arsenic trioxide exposure may increase in patients with severe renal impairment (creatinine clearance <30 mL/minute); consider dosage reduction if needed.1 Arsenic trioxide has not been studied in patients receiving dialysis.1
The manufacturer makes no specific dosage recommendations in geriatric patients.1
Differentiation syndrome, including life-threatening or fatal cases, has occurred in patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide, with reported rates of 16‒23% in clinical trials.1 A boxed warning about this risk has been included in the prescribing information.1 Differentiation syndrome may occur with or without leukocytosis and may develop as early as day 1 or as late as the second month of induction therapy.1 Signs and symptoms include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusion, weight gain, edema, hypotension, renal insufficiency, hepatopathy, and multiorgan dysfunction.1 If signs or symptoms occur, immediately administer dexamethasone 10 mg IV every 12 hours for at least 3 days; continue until signs and symptoms resolve.1 When arsenic trioxide is used with tretinoin, administer prednisone prophylaxis during induction.1
Cardiac Conduction Abnormalities
Arsenic trioxide may cause QT interval corrected (QTc) prolongation, complete atrioventricular (AV) block, and torsade de pointes.1 A boxed warning about this risk has been included in the prescribing information.1 In clinical trials, QTc prolongation occurred in 11% of patients with newly diagnosed low-risk APL receiving arsenic trioxide plus tretinoin and in 40% of patients with relapsed or refractory APL receiving arsenic trioxide alone.1 QTc prolongation was observed 1‒5 weeks after treatment initiation and usually resolved by 8 weeks.1
Before starting therapy, obtain an ECG, correct electrolyte abnormalities, and avoid or discontinue concomitant QT-prolonging drugs when possible.1 During treatment, maintain potassium >4 mEq/L and magnesium >1.8 mg/dL, monitor ECG weekly and more often in clinically unstable patients.1 Withhold arsenic trioxide if QTc exceeds 450 msec in men or 460 msec in women until the QTc normalizes and electrolyte abnormalities are corrected, then restart at a reduced dosage.1
Arsenic trioxide has been associated with serious encephalopathies, including Wernicke's encephalopathy.1 A boxed warning about this risk has been included in the prescribing information.1 Monitor patients for neurologic symptoms such as confusion, decreased consciousness, seizures, cognitive impairment, ataxia, visual symptoms, and ocular motor dysfunction, and monitor nutritional status during treatment.1 Consider checking thiamine levels in patients at risk for deficiency, and administer parenteral thiamine to patients with or at risk for thiamine deficiency.1 If Wernicke encephalopathy is suspected, immediately interrupt arsenic trioxide therapy and start parenteral thiamine; monitor patients until symptoms improve or resolve and thiamine levels normalize.1
In clinical trials, hepatotoxicity occurred in 44% of patients with newly diagnosed low-risk APL receiving arsenic trioxide plus tretinoin and generally resolved with temporary interruption of treatment.1 Long-term hepatic abnormalities, including mild liver dysfunction and hepatic steatosis, have also been reported after treatment.1 Monitor hepatic function tests at least twice weekly during induction and at least weekly during consolidation therapy, and withhold arsenic trioxide and/or tretinoin for AST or alkaline phosphatase >5 times the upper limit of normal (ULN) and/or total bilirubin >3 times the ULN; resume at a reduced dose after recovery.1
Arsenic trioxide is a human carcinogen; monitor for secondary malignancies.1
Fetal/Neonatal Morbidity and Mortality
Arsenic trioxide may cause fetal harm; animal studies showed embryofetal toxicity and birth defects with arsenic exposure.1 Advise pregnant women of the fetal risk.1 Females of reproductive potential should use effective contraception during treatment and for 6 months after the last dose; males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose.1
Arsenic trioxide can cause fetal harm; animal studies showed embryofetal toxicity and teratogenic effects.1 Advise pregnant women of the potential fetal risk.1
Females of reproductive potential should use effective contraception during treatment and for 6 months after the last dose; males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose.1
Arsenic trioxide is excreted into human milk.1 There are no data on the effects of arsenic trioxide on the breastfed child or on milk production.1 Advise women not to breastfed during treatment and for 2 weeks after the final dose.1
Females and Males of Reproductive Potential
Arsenic trioxide can cause fetal harm when administered to a pregnant woman.1 Verify pregnancy status in women of reproductive potential before beginning therapy.1 Advise women of reproductive potential to use effective contraception during therapy and for 6 months after the final dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose.1 Arsenic trioxide may impair fertility in males of reproductive potential by decreasing testicular weight and impairing spermatogenesis.1
The safety and efficacy of arsenic trioxide in combination with tretinoin have not been established in pediatric patients.1 Evidence supporting the use of single-agent arsenic trioxide in pediatric patients with relapsed or refractory APL is derived from a phase 2 study that included 5 patients <18 years of age in addition to data from published studies which included 17 additional patients 4‒21 years of age.1 No age-related differences in safety or efficacy were observed.1
There are limited data with use of arsenic trioxide in patients with hepatic impairment; use with caution in patients with hepatic impairment and monitor patients with severe hepatic impairment closely for toxicity.1
The exposure to arsenic trioxide may be higher in patients with severe renal impairment.1 Monitor patients with severe renal impairment (creatinine clearance <30 mL/minute) frequently for toxicity; dosage adjustment may be needed.1
The most common adverse reactions reported in more than 30% of patients receiving arsenic trioxide in clinical studies were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus.1
No formal drug interaction studies have been conducted to date with arsenic trioxide.1
Drugs that Can Prolong the QT Interval
Concomitant use of arsenic trioxide with other drugs that prolong the QT or QT interval corrected for rate (QTc) may further increase the risk of serious QT/QTc prolongation.1 Discontinue or replace these agents when possible; if coadministration cannot be avoided, monitor ECG more frequently.1
Drugs that Can Lead to Electrolyte Abnormalities
Electrolyte abnormalities increase the risk of serious QT/QTc prolongation.1 Avoid concomitant use of drugs that can cause electrolyte disturbances; if use cannot be avoided, monitor electrolytes more frequently during arsenic trioxide therapy.1
Drugs that Can Lead to Hepatotoxicity
Concomitant use of hepatotoxic drugs with arsenic trioxide, especially in combination with tretinoin, may increase the risk of serious hepatotoxicity.1 Discontinue or replace these medications when possible; if coadministration cannot be avoided, monitor liver function tests more frequently.1
Arsenic trioxide is an antineoplastic agent.1 The mechanism of action of arsenic trioxide is not fully understood, but it appears to induce apoptosis and promote degradation of the promyelocytic leukemia retinoic acid receptor alpha (PML-RARα) fusion protein.1
The pharmacokinetics of trivalent arsenic have not been fully characterized.1 After dilution in the syringe, arsenic trioxide converts to arsenious acid, the active form.1 Exposure appears proportional to dosage, and peak plasma concentrations occur by the end of the 2-hour infusion, followed by a biphasic decline and modest accumulation with repeated dosing.1 Arsenic distributes widely throughout body tissues, and the volume of distribution increases with body weight.1 The liver extensively metabolizes arsenious acid through methyltransferases rather than cytochrome P-450 isoenzymes, producing monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), with smaller amounts of arsenic acid, which remain at low plasma concentrations.1 Compared with the active form, the metabolites reach measurable plasma concentrations later, have longer half-lives, and accumulate to a greater extent with repeated dosing.1 About 15% of arsenic trioxide is excreted unchanged in the urine.1 The half-life is 10 to 14 hours for arsenious acid, 32 hours for MMAV, and 72 hours for DMAV.1 Exposure increases by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/minute); in one patient with severe hepatic impairment (Child-Pugh class C), arsenic exposure increased by 40‒70%.1 Arsenic trioxide does not inhibit the metabolism of substrates of major CYP isoenzymes, including 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use only | 2 mg/mL (12 mg)* | Arsenic Trioxide Injection | |
1 mg/mL (10 mg)* | Arsenic Trioxide Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Teva Pharmaceuticals for Cephalon. Trisenox® (arsenic trioxide) injection prescribing information. Parsippany, NJ; 2022 Jun
2. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19(18):3852-3860. doi:10.1200/JCO.2001.19.18.3852
3. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121. doi:10.1056/NEJMoa1300874
4. National Institute for Occupational Safety and Health. NIOSH List of Hazardous Drugs in Healthcare Settings, 2024. Centers for Disease Control and Prevention; 2025. Accessed March 25, 2026 [Web]
5. Zydus Pharmaceuticals. Arsenic trioxide injection for IV use prescribing information. Pennington, NJ; 2025 Feb.
6. Iyer SG, Elias L, Stanchina M, Watts J. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions. Front Oncol. 2023;12:1062524. Published 2023 Jan 18. doi:10.3389/fonc.2022.1062524
7. Sanz MA, Fenaux P, Tallman MS, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133(15):1630-1643. doi:10.1182/blood-2019-01-894980
8. Osman AEG, Anderson J, Churpek JE, et al. Treatment of Acute Promyelocytic Leukemia in Adults. J Oncol Pract. 2018;14(11):649-657. doi:10.1200/JOP.18.00328
9. National Cancer Institute. Acute Myeloid Leukemia Treatment (PDQ®)-Health Professional Version. PDQ Cancer Information Summaries. Updated March 14, 2025. Accessed March 28, 2026. [Web]
10. Childhood Acute Promyelocytic Leukemia Treatment (PDQ®)-Health Professional Version. Updated Kune 14, 2024. Accessed March 28, 2026. [Web]
11. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2026 Mar 29 [Web]
12. Zydus Pharmaceuticals. Arsenic trioxide injection for IV use prescribing information. Pennington, NJ; 2025 Feb.