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Arsenic Trioxide

Medically reviewed by Drugs.com. Last updated on Jul 18, 2019.

Pronunciation

(AR se nik tri OKS id)

Index Terms

  • Arsenic (III) Oxide
  • As2O3
  • ATO

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Trisenox: 10 mg/10 mL (10 mL [DSC])

Generic: 10 mg/10 mL (10 mL)

Solution, Intravenous [preservative free]:

Trisenox: 12 mg/6 mL (6 mL)

Generic: 10 mg/10 mL (10 mL); 12 mg/6 mL (6 mL)

Brand Names: U.S.

  • Trisenox

Pharmacologic Category

  • Antineoplastic Agent, Miscellaneous

Pharmacology

Arsenic trioxide induces apoptosis in APL cells via morphological changes and DNA fragmentation; also damages or degrades the fusion protein promyelocytic leukemia (PML)-retinoic acid receptor (RAR) alpha

Distribution

Vdss: Arsenious acid (AsIII): 562 L; widely distributed throughout body tissues; dependent on body weight and increases as body weight increases; orally administered arsenic trioxide distributes into the CNS

Metabolism

Arsenic trioxide is immediately hydrolyzed to the active form, arsenious acid (AsIII) which is methylated (hepatically) to the less active pentavalent metabolites, monomethylarsonic acid (MMAv) and dimethylarsinic acid (DMAv) by methyltransferases; AsIII is also oxidized to the minor metabolite, arsenic acid (Asv)

Excretion

Urine (MMAv, DMAv, and ~15% of a dose as unchanged AsIII)

Time to Peak

AsIII: At the end of infusion (2 hours); MMAv and DMAv; ~10 to 24 hours

Half-Life Elimination

AsIII: 10 to 14 hours; MMAv: ~32 hours; DMAv: ~72 hours

Special Populations: Renal Function Impairment

Results from a pharmacokinetic study in patients with advanced malignancies showed that mean AUC for AsIII was ~48% higher in patients with several renal impairment (CrCl <30 mL/minute) than in patients with normal renal function (CrCl >80 mL/minute). Systemic exposure to metabolites MMAV and DMAV may also be increased in patients with renal impairment.

Special Populations: Hepatic Function Impairment

A small pharmacokinetic study in patients with hepatocellular carcinoma showed that the mean dose-normalized AUC and Cmax values were 40% and 70% higher, respectively, in a patient with severe hepatic impairment (Child-Pugh class C) versus patients with normal hepatic function. Additionally, the mean dose-normalized trough plasma levels for metabolites MMAV and DMAV were 2.2-fold and 4.7-fold higher, respectively, than levels in patients with normal hepatic function.

Use: Labeled Indications

Acute promyelocytic leukemia (newly diagnosed) (low-risk disease): Treatment of newly diagnosed low-risk acute promyelocytic leukemia (APL), in combination with tretinoin, in adults whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Acute promyelocytic leukemia (relapsed or refractory): Remission induction and consolidation treatment of APL in patients who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Off Label Uses

Acute promyelocytic leukemia (newly diagnosed) (including intermediate- or high-risk disease)

Data from a randomized, multicenter, phase III study support the use of arsenic trioxide (in combination with tretinoin) in the management of intermediate-risk acute promyelocytic leukemia (APL) [Lo-Coco 2013], [Platzbecker 2017]. Data from a phase III study support the use of arsenic trioxide as a part of consolidation therapy in intermediate- and high-risk patients [Powell 2010]. Data from a phase III study support the use of arsenic (in combination with tretinoin and [for high-risk patients] gemtuzumab ozogamicin) for the treatment of newly diagnosed APL in all risk groups [Burnett 2015]. Data from a phase II study support the use of arsenic trioxide (in combination with tretinoin) for the treatment of APL in patients with intermediate-risk disease and (in combination with tretinoin and gemtuzumab ozogamicin) in patients with high-risk disease [Estey 2006], [Ravandi 2009]. Data from another phase II study support the use of arsenic trioxide (in combination with tretinoin and idarubicin) for the treatment of APL in all risk groups [Iland 2012]. These studies also included patients with newly diagnosed low-risk APL, which is a labeled indication.

Contraindications

Hypersensitivity to arsenic or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Pregnancy; breast-feeding

Dosing: Adult

Note: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Acute promyelocytic leukemia (APL), newly diagnosed, low-risk: IV: Note: Prophylaxis for differentiation syndrome with prednisone 0.5 mg/kg/day is recommended starting on day 1 and continuing until the end of induction.

Induction (1 cycle): 0.15 mg/kg once daily (in combination with tretinoin); continue until bone marrow remission, not to exceed 60 days (Lo-Coco 2013; Platzbecker 2017)

Consolidation (4 cycles): 0.15 mg/kg once daily for 5 days each week during weeks 1 to 4 of each 8-week consolidation cycle (in combination with tretinoin) for a total of 4 consolidation cycles (Lo-Coco 2013; Platzbecker 2017)

APL (newly diagnosed, including intermediate- and/or high-risk disease) (off-label): IV:

APL0406 protocol: Intermediate-risk (Lo-Coco 2013; Platzbecker 2017):

Induction (1 cycle): 0.15 mg/kg once daily (in combination with tretinoin); continue until bone marrow remission, not to exceed 60 days

Consolidation (4 cycles): 0.15 mg/kg once daily for 5 days each week during weeks 1 to 4 of each 8-week consolidation cycle (in combination with tretinoin) for a total of 4 consolidation cycles

AML17 protocol (low-, intermediate-, or high-risk); in combination with tretinoin (Burnett 2015):

Induction (cycle 1): 0.3 mg/kg once daily on days 1 to 5 in week 1, followed by 0.25 mg/kg twice a week during weeks 2 to 8; high-risk patients were also administered a single dose of gemtuzumab within the first 4 days of treatment.

Consolidation (cycles 2 to 5): 0.3 mg/kg once daily on days 1 to 5 in week 1, followed by 0.25 mg/kg twice a week during weeks 2 to 4

C9710 protocol (low-, intermediate-, or high-risk); following remission induction with tretinoin, daunorubicin, and cytarabine, and followed by tretinoin (Powell 2010): Consolidation (2 courses): 0.15 mg/kg once daily on days 1 to 5 in each week during weeks 1 to 5; each course is separated by 2 weeks

Low-, intermediate-, or high-risk patients unable to tolerate anthracycline-based therapy; in combination with tretinoin (Estey 2006; Ravandi 2009):

Induction (1 cycle; beginning 10 days after initiation of tretinoin): 0.15 mg/kg once daily until bone marrow remission; maximum: 75 doses for induction; high-risk patients were also administered gemtuzumab on day 1 of induction

Consolidation (4 cycles): 0.15 mg/kg once daily on Monday through Friday for 4 weeks of every 8-week treatment cycle for 4 cycles (weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28)

APML4 protocol (low-, intermediate- and high-risk) (Iland 2012):

Induction (1 cycle): 0.15 mg/kg once daily on days 9 to 36 (in combination with tretinoin and age-adjusted idarubicin)

Consolidation (2 cycles): 0.15 mg/kg once daily on days 1 to 28 of consolidation cycle 1 (in combination with tretinoin); 0.15 mg/kg once daily on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33 of consolidation cycle 2 (in combination with tretinoin)

APL (relapsed or refractory): IV:

Induction (1 cycle): 0.15 mg/kg once daily until bone marrow remission; maximum: 60 doses for induction

Consolidation (1 cycle): 0.15 mg/kg once daily for 25 doses over a period of up to 5 weeks, beginning 3 to 6 weeks after completion of induction therapy

Dosing: Pediatric

Note: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011)

Acute promyelocytic leukemia (APL), initial treatment: Limited data available:

Single-agent (Mathews 2006): Children and Adolescents: Dosing based on experience available for children ≥3 years; however, age was not an exclusion criteria in clinical trial

Induction: IV: 0.15 mg/kg/day (maximum dose: 10 mg/dose); administer daily until bone marrow remission; maximum induction: 60 doses

Consolidation: IV: 0.15 mg/kg/day (maximum dose: 10 mg/dose) for 4 weeks, starting 4 weeks after completion of induction therapy

Maintenance: IV: 0.15 mg/kg/dose (maximum dose: 10 mg/dose) administered 10 days per month for 6 months, starting 4 weeks after completion of consolidation therapy

In combination with tretinoin and gemtuzumab in high-risk APL (Ravandi 2009): Children and Adolescents: Dosing based on experience available for adolescents ≥14 years; however, age was not an exclusion criteria in clinical trial

Induction (beginning 10 days after initiation of tretinoin): IV: 0.15 mg/kg/day until bone marrow remission; maximum induction: 75 doses

Consolidation: IV: 0.15 mg/kg/day Monday through Friday for 4 weeks every 8 weeks for 4 cycles (weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28)

In combination with tretinoin, idarubicin, and prednisone (APML4 protocol) (Iland 2012): Children >1 year and Adolescents:

Induction: IV: 0.15 mg/kg/day over 2 hours on days 9 to 36 (in combination with tretinoin and idarubicin)

Consolidation: IV: 0.15 mg/kg/day on days 1 to 28 of consolidation cycle 1 (in combination with tretinoin); 0.15 mg/kg/day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33 of consolidation cycle 2 (in combination with tretinoin); 2 cycles total

Acute promyelocytic leukemia (APL), relapsed or refractory: Children ≥4 years and Adolescents:

Induction: IV: 0.15 mg/kg/day; administer daily until bone marrow remission; maximum induction: 60 doses

Consolidation: IV: 0.15 mg/kg/day starting 3 to 6 weeks after completion of induction therapy; maximum consolidation: 25 doses over a period of up to 5 weeks

Dosing adjustment for toxicity:

Acute promyelocytic leukemia (APL), relapsed or refractory: Children ≥4 years and Adolescents: IV:

Dosage reduction levels (for hematologic and nonhematologic toxicities):

Initial dosage: 0.15 mg/kg once daily

First dose reduction level: 0.11 mg/kg once daily

Second dose reduction level: 0.1 mg/kg once daily

Third dose reduction level: 0.075 mg/kg once daily

Dosage adjustment when used alone or in combination with tretinoin: Refer to tretinoin monograph for additional information.

Hematologic toxicities:

Leukocytosis (WBC >10,000/mm3): Administer hydroxyurea; may discontinue hydroxyurea when WBC declines to <10,000/mm3.

ANC <1,000/mm3: Consider reducing the arsenic trioxide dose by 1 dose level. If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide at 1 dose level lower.

Platelets <50,000/mm3: Consider reducing the arsenic trioxide dose by 1 dose level. If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide at 1 dose level lower.

Nonhematologic toxicities:

Differentiation syndrome (defined as the presence of 2 or more of the following: Unexplained fever, dyspnea, pleural and/or pericardial effusion, pulmonary infiltrates, renal failure, hypotension, weight gain >5 kg): Temporarily withhold arsenic trioxide and begin IV dexamethasone every 12 hours until resolution of signs/symptoms for a minimum of 3 days. When clinical condition improves, resume treatment with the dose reduced by 50%. After 7 days, in the absence of recurrent symptoms, increase the dose to the recommended dosage. If symptoms recur, decrease arsenic trioxide to the previous dose.

QTc prolongation >450 msec (for males) or >460 msec (for females): Withhold arsenic trioxide and any other medication known to prolong the QTc interval. Replete electrolytes. After the QTc normalizes, resume arsenic trioxide with a 50% dose reduction (to 0.075 mg/kg once daily) for 7 days. If the 50% dose reduction is tolerated for 7 days, in the absence of QTc prolongation, increase the arsenic trioxide dose to 0.11 mg/kg once daily for 7 days. In the absence of QTc prolongation, the dose may be further increased to 0.15 mg/kg once daily during the 14-day dose escalation period.

Other nonhematologic reactions:

Moderate (grade 2): Reduce the arsenic trioxide dose by 1 dose level.

Severe or life-threatening (grade 3 or 4): Temporarily withhold arsenic trioxide. When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide with the dose reduced by 2 dose levels.

Dosing: Adjustment for Toxicity

Dosage reduction levels (for hematologic and nonhematologic toxicities; tretinoin may also require dose reduction):

Initial dosage: 0.15 mg/kg once daily

First dose reduction level: 0.11 mg/kg once daily

Second dose reduction level: 0.1 mg/kg once daily

Third dose reduction level: 0.075 mg/kg once daily

Dosage adjustment when used alone or in combination with tretinoin:

Hematologic toxicities:

Leukocytosis (WBC >10,000/mm3): Administer hydroxyurea; may discontinue hydroxyurea when WBC declines to <10,000/mm3.

ANC <1,000/mm3: Consider reducing the dose (arsenic trioxide and tretinoin) by 1 dose level. If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide (and tretinoin) at 1 dose level lower.

Platelets <50,000/mm3(lasting >5 weeks): Consider reducing the dose (arsenic trioxide and tretinoin) by 1 dose level. If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide (and tretinoin) at 1 dose level lower.

Nonhematologic toxicities:

Differentiation syndrome (defined as the presence of 2 or more of the following: Unexplained fever, dyspnea, pleural and/or pericardial effusion, pulmonary infiltrates, renal failure, hypotension, weight gain >5 kg): Temporarily withhold arsenic trioxide (consider withholding tretinoin if severe) and begin dexamethasone 10 mg IV every 12 hours until resolution of signs/symptoms for a minimum of 3 days. When clinical condition improves, resume treatment with the dose of the withheld drug(s) reduced by 50%. After 7 days, in the absence of recurrent symptoms, increase the dose to the recommended dosage. If symptoms recur, decrease arsenic and/or tretinoin to the previous dose.

QTc prolongation >450 msec (for males) or >460 msec (for females): Withhold arsenic trioxide and any medication known to prolong the QTc interval. Replete electrolytes. After the QTc normalizes, resume arsenic trioxide with a 50% dose reduction (to 0.075 mg/kg once daily) for 7 days. If the 50% dose reduction is tolerated for 7 days, in the absence of QTc prolongation, increase the arsenic trioxide dose to 0.11 mg/kg once daily for 7 days. In the absence of QTc prolongation, the dose may be further increased to 0.15 mg/kg once daily during the 14-day dose escalation period.

Other nonhematologic reactions:

Moderate (grade 2): Reduce the dose (arsenic trioxide and/or tretinoin) by 1 dose level.

Severe or life-threatening (grade 3 or 4): Temporarily withhold arsenic trioxide and tretinoin. When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide and tretinoin with the dose reduced by 2 dose levels.

Reconstitution

Multiple concentrations: Arsenic trioxide is available as a 2 mg/mL solution (vial); previously, it was available as a 1 mg/mL solution (ampule). Verify concentration prior to admixture to assure appropriate dose preparation.

Dilute with 100 to 250 mL D5W or NS; dilute immediately after withdrawal from vial (discard unused portion of vial/ampule; do not save unused portion for later administration). Do not mix with other medications.

Administration

IV: Infuse over 2 hours. If acute vasomotor reactions occur, the infusion duration may be extended to up to 4 hours. Arsenic trioxide does not require administration via a central venous catheter.

Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Storage

Store intact vials/ampules at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Following dilution in D5W or NS, solutions diluted for infusion are stable for 24 hours at room temperature or 48 hours when refrigerated.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amiodarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Amisulpride: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Avoid combination

Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Avoid combination

Doxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Dronedarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Dronedarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Droperidol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Droperidol. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Fluconazole: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Avoid combination

Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gemifloxacin: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Consider therapy modification

Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Haloperidol: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Levofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Methadone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Avoid combination

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Avoid combination

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Avoid combination

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Propafenone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone. Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Miscellaneous Agents (Highest Risk): May enhance the QTc-prolonging effect of Arsenic Trioxide. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Fluconazole; Nilotinib; Ribociclib. Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Exceptions: Clarithromycin. Avoid combination

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Avoid combination

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Avoid combination

RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sodium Stibogluconate: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Avoid combination

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Avoid combination

Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Tachycardia (55%), edema (40%), prolonged QT interval on ECG (40%; >500 msec), chest pain (25%), hypotension (25%)

Central nervous system: Fatigue (63%), headache (60%), insomnia (43%), rigors (38%), paresthesia (33%), anxiety (30%), dizziness (23%), depression (20%), pain (15%)

Dermatologic: Dermatitis (43%), pruritus (33%), xeroderma (15%), diaphoresis (13%), erythema of skin (13%)

Endocrine & metabolic: Hypokalemia (50%), hyperglycemia (45%), hypomagnesemia (45%), hyperkalemia (18%), weight gain (13%)

Gastrointestinal: Nausea (75%), abdominal pain (58%), vomiting (58%), diarrhea (53%), sore throat (35%), constipation (28%), anorexia (23%), decreased appetite (15%)

Genitourinary: Vaginal hemorrhage (13%)

Hematologic & oncologic: Leukocytosis (50%; grades 3/4: 3%), differentiation syndrome (16% to 23%; grades 3/4: 8%), anemia (20%; grades 3/4: 5%), bruise (20%), thrombocytopenia (18%; grades 3/4: 13%), febrile neutropenia (13%; grades 3/4: 8%)

Hepatic: Increased serum alanine aminotransferase (20%), increased serum aspartate aminotransferase (13%)

Infection: Herpes simplex infection (13%)

Local: Pain at injection site (20%), erythema at injection site (13%)

Neuromuscular & skeletal: Arthralgia (33%), myalgia (25%), ostealgia (23%), back pain (18%), limb pain (13%), neck pain (13%), tremor (13%)

Respiratory: Cough (65%), dyspnea (53%), epistaxis (25%), hypoxia (23%), pleural effusion (20%), sinusitis (20%), post nasal drip (13%), upper respiratory tract infection (13%), wheezing (13%)

Miscellaneous: Fever (63%)

1% to 10%:

Cardiovascular: Hypertension (10%), flushing (10%), palpitations (10%), ECG abnormality (8%; non-QT prolongation), facial edema (8%), atrial arrhythmia (5%), torsades de pointes (3%)

Central nervous system: Drowsiness (8%), seizure (8%), agitation (5%), coma (5%), confusion (5%)

Dermatologic: Pallor (10%), hyperpigmentation (8%), night sweats (8%), skin lesion (8%), urticaria (8%)

Endocrine & metabolic: Hypocalcemia (10%), hypoglycemia (8%), intermenstrual bleeding (8%), weight loss (8%), acidosis (5%)

Gastrointestinal: Dyspepsia (10%), loose stools (10%), abdominal distension (8%), abdominal tenderness (8%), bloody diarrhea (8%), fecal incontinence (8%), gastrointestinal hemorrhage (8%), oral bullae (8%), xerostomia (8%), oral candidiasis (5%)

Genitourinary: Oliguria (5%), urinary incontinence (5%)

Hematologic & oncologic: Neutropenia (10%; grades 3/4: 10%), disseminated intravascular coagulation (8%; grades 3/4: 8%), hemorrhage (8%), hyperleukocytosis (grades 3/4: 8%), lymphadenopathy (8%), petechia (8%)

Hypersensitivity: Hypersensitivity reaction (5%)

Infection: Bacterial infection (8%), herpes zoster infection (8%), sepsis (5%)

Local: Swelling at injection site (10%), local skin exfoliation (5%)

Neuromuscular & skeletal: Asthenia (10%)

Ophthalmic: Blurred vision (10%), eye irritation (10%), xerophthalmia (8%), eye redness (with pain: 5%), eyelid edema (5%)

Otic: Otalgia (8%), tinnitus (5%)

Renal: Renal failure syndrome (8%), renal insufficiency (8%)

Respiratory: Abnormal breath sounds (decreased: 10%), rales (10%), hemoptysis (8%), rhonchi (8%), tachypnea (8%), nasopharyngitis (5%)

<1%, postmarketing, and/or case reports: Atrioventricular block, bone marrow failure (necrosis), cardiac failure, deafness, encephalopathy (including Wernicke's), heart block, increased gamma-glutamyl transferase, malignant melanoma, pancytopenia, paresis, peripheral neuropathy, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, squamous cell carcinoma, toxic epidermal necrolysis, ventricular premature contractions, ventricular tachycardia

ALERT: U.S. Boxed Warning

Differentiation syndrome:

Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multiorgan dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Temporary discontinuation of arsenic trioxide may be required.

QT prolongation:

Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a torsade des pointes-type ventricular arrhythmia, which can be fatal. Before initiating therapy, assess the QTc interval, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide to patients with ventricular arrhythmia or prolonged QTcF.

Encephalopathy:

Serious encephalopathy, including Wernicke, has occurred in patients treated with arsenic trioxide. Wernicke encephalopathy is a neurologic emergency. Consider testing thiamine levels in patients at risk for thiamine deficiency. Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving arsenic trioxide. If encephalopathy is suspected, immediately interrupt arsenic trioxide and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: [US Boxed Warning]: Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide have experienced symptoms of differentiation syndrome (may be fatal if not treated). Symptoms may include fever (unexplained), dyspnea, acute respiratory distress, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multiorgan dysfunction, occurring with or without leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until signs/symptoms resolve. May require temporary discontinuation of arsenic trioxide. The onset of differentiation syndrome has occurred as early as day 1 of induction to as late as the second month of induction therapy. Prophylaxis with prednisone is recommended when arsenic trioxide is used in combination with tretinoin. At the first signs of differentiation syndrome, interrupt arsenic trioxide and administer dexamethasone 10 mg IV twice daily; continue high-dose corticosteroids until signs/symptoms have abated for at least 3 days.

• Encephalopathy: [US Boxed Warning]: Serious encephalopathy, including Wernicke, has been reported with use. Consider testing thiamine levels in patients at risk for thiamine deficiency; administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status during therapy. If encephalopathy is suspected, immediately interrupt arsenic trioxide and initiate parenteral thiamine; monitor until symptoms resolve or improve and thiamine levels normalize.

• Gastrointestinal toxicity: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

• Hepatotoxicity: In newly diagnosed low-risk APL studies, almost half of the patients treated with arsenic trioxide in combination with tretinoin experienced elevated AST, alkaline phosphatase, and/or serum bilirubin, which usually resolved with temporary discontinuation of arsenic trioxide and/or tretinoin. Monitor LFTs at least 2 to 3 times a week during arsenic trioxide treatment and continue monitoring until toxicity recovers. Withhold arsenic trioxide treatment and/or tretinoin if AST, alkaline phosphatase, and/or serum bilirubin elevations >5 times the ULN occur. Long-term hepatic abnormalities may occur in patients with APL treated with arsenic trioxide in combination with tretinoin. Mild hepatic dysfunction and hepatic steatosis have been observed at a median of 7 years (range: up to 14 years) following arsenic trioxide and tretinoin combination therapy.

• QT prolongation: [US Boxed Warning]: Arsenic trioxide may cause QTc interval prolongation, atrioventricular block, and a torsade des pointes-type ventricular arrhythmia, which may be fatal. Prior to treatment initiation, assess the QTc interval (by ECG), correct preexisting electrolyte abnormalities, and consider discontinuing medications known to prolong QTc interval. Do not administer arsenic trioxide to patients with ventricular arrhythmia or prolonged QTcF. In newly diagnosed low-risk APL studies, some patients who received arsenic trioxide in combination with tretinoin experienced QTc prolongation >450 msec (for males) and >460 msec (for females) throughout treatment cycles. In studies for relapsed or refractory APL, over one-third of patients who received arsenic trioxide (as monotherapy) had at least one ECG with a QTc interval >500 msec. Prolonged QTc has been observed between 1 and 5 weeks after start of arsenic trioxide treatment, and usually resolved by 8 weeks after treatment. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion. The risk of torsades de pointes is related to the extent of QTc prolongation, concurrent use of QTc prolonging medications, a history of torsade des pointes, preexisting QTc interval prolongation, heart failure, concurrent potassium-wasting diuretics, or other conditions associated with hypokalemia or hypomagnesemia. The risk may be increased when arsenic trioxide is coadministered with medications associated with electrolyte abnormalities (eg, diuretics or amphotericin B). If it is not possible to discontinue concomitant medications associated with QTc prolongation, perform cardiac monitoring frequently. Maintain serum potassium >4 mEq/L and magnesium >1.8 mg/dL during treatment. Monitor ECG weekly (more frequently in clinically unstable patients). If QTc >500 msec develops, immediately withhold arsenic trioxide treatment and any medication known to prolong the QTc interval and correct electrolyte abnormalities; when the QTc normalizes, resume arsenic trioxide at a reduced dose.

• Secondary malignancy: Arsenic trioxide is a human carcinogen; monitor for the development of second primary malignancies.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; monitor closely for toxicity in patients with severe hepatic impairment.

• Renal impairment: Use with caution in patients with severe renal impairment (CrCl <30 mL/minute); systemic exposure may be higher. Dose reduction may be warranted; monitor closely for toxicities. Arsenic trioxide has not been studied in dialysis patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Multiple concentrations: Arsenic trioxide is available in different concentrations; verify concentration prior to admixture to assure appropriate dose preparation.

Monitoring Parameters

Monitor electrolytes (potassium, calcium, and magnesium), CBC with differential, renal function (serum creatinine), hepatic function, blood glucose, and coagulation parameters at baseline then at least 2 to 3 times a week during induction and at least weekly during consolidation; more frequent monitoring may be necessary in unstable patients; pregnancy test (prior to treatment in females of reproductive potential); baseline then weekly 12-lead ECG; signs/symptoms of APL differentiation syndrome (unexplained fever, dyspnea, and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities); signs/symptoms of encephalopathy after initiation.

Pregnancy Considerations

Arsenic trioxide crosses the placenta (Concha 1998).

Based on the mechanism of action and findings in animal reproduction studies, arsenic trioxide may cause fetal harm if administered during pregnancy.

Aresnic trioxine occurs naturally and toxicity varies between organic and inorganic forms (IOM 2000). In studies of women exposed to high levels of arsenic from drinking water, cord blood levels were similar to maternal serum levels. Dimethylarsinic acid (DMA) was the form of arsenic found in the fetus. An increased risk of low birth weight and still births were observed in women who ingested high levels of dietary arsenic (Concha 1998; von Ehrenstein 2006; Yang 2003).

Available leukemia guidelines note arsenic trioxide is teratogenic and should not be used at any time during pregnancy (Lishner 2016; Sanz 2019).

Females should be advised against conceiving during treatment with arsenic trioxide (Sanz 2019). Verify pregnancy status in females of reproductive potential prior to initiating therapy. Females of reproductive potential should use effective contraception during treatment and for 6 months after the final arsenic trioxide dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the final arsenic trioxide dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, abdominal pain, diarrhea, lack of appetite, weight gain, weight loss, dry mouth, insomnia, fatigue, bone pain, injection site pain or irritation, dry eyes, pale skin, anxiety, joint pain, muscle pain, back pain, sweating a lot, painful extremities, dry skin, flushing, neck pain, ear pain, skin irritation, or eye irritation. Have patient report immediately to prescriber abnormal heartbeat, signs of retinoic-acid-APL syndrome (fever, shortness of breath, difficulty breathing, or weight gain), signs of infection, signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), confusion, severe fatigue, change in balance, difficulty thinking, difficulty walking, chest pain, tachycardia, abnormal heartbeat, severe dizziness, passing out, severe headache, vision changes, severe loss of strength and energy, enlarged lymph nodes, depression, seizures, burning or numbness feeling, tremors, fast breathing, agitation, tinnitus, or abdominal edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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