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Arsenic Trioxide: Side Effects, Uses, Dosage, Interactions, Warnings

Arsenic Trioxide

What Is Arsenic Trioxide Used For and How Does it Work?

Arsenic trioxide is used to treat acute promyelocytic leukemia (APL).

Arsenic trioxide is available under the following different brand names: Trisenox.

What Are the Dosages of Arsenic Trioxide?

Dosages of Arsenic Trioxide:

Adult and Pediatric Dosage Forms and Strengths

Injectable Solution

  • 1 mg/mL (10mg ampule)

Dosage Considerations – Should be Given as Follows:

Acute Promyelocytic Leukemia

Newly diagnosed low-risk acute promyelocytic leukemia (APL)

  • Indicated in combination with tretinoin for treatment of adults with newly diagnosed low-risk APL whose APL has the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
  • The treatment course consists of 1 induction and 4 consolidation cycles
  • Induction cycle
    • Arsenic trioxide 0.15 mg/kg intravenously (IV) once daily until bone marrow remission; not to exceed 60 days, PLUS
    • Tretinoin 22.5 mg/m2 orally twice daily until bone marrow remission; not to exceed 60 days
    • Differentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day 1 until the end of induction therapy is recommended
  • Consolidation cycle
    • Arsenic trioxide 0.15 mg/kg IV daily x Days 1-5 on Weeks 1-4 of an 8-week cycle for a total of 4 cycles in combination with tretinoin
    • Tretinoin 22.5 mg/m2 orally twice daily x Days 1-7 on Weeks 1, 2, 5, 6; omit tretinoin during weeks 5-6 of the fourth cycle of consolidation

Relapsed or refractory APL, Adult

  • Indicated for induction of remission and consolidation in patients with APL 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
  • The treatment course consists of 1 induction and 1 consolidation cycle
  • Induction cycle
    • Arsenic trioxide 0.15 mg/kg IV once daily until bone marrow remission; not to exceed 60 days
  • Consolidation Cycle
    • Begin consolidation 3-6 weeks after completion of induction therapy
    • Arsenic trioxide 0.15 mg/kg IV daily for 25 doses for up to 5 weeks

Refractory or relapse after retinoid and anthracycline chemotherapy, Pediatric

  • Indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) 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
  • Children under 4 years: Safety and efficacy not established
  • Children 4 years and older: 0.15 mg/kg IV once daily until bone marrow remission; not to exceed 60 doses
  • Wait 3-6 weeks, THEN
  • 0.15 mg/kg IV once daily for 25 doses (administered overtime period of up to 5 weeks)

Dosage Modifications

Differentiation syndrome

  • Defined by the presence of 2 or more of the following: Unexplained fever, shortness of breath; pleural and/or pericardial effusion; pulmonary infiltrates; renal failure; hypotension; weight gain greater than 5 kg
  • Temporarily withhold arsenic trioxide
  • Consider holding tretinoin if symptoms are severe
  • Treat with dexamethasone 10 mg IV every 12 hours until resolution of signs and symptoms for a minimum of 3 days
  • Resume treatment when the clinical condition improves and reduce the dose of the withheld drug(s) by 50%
  • After 7 days on the reduced dose in the absence of differentiation syndrome, increase the dose of the withheld drug(s) to the recommended dosage
  • If symptoms reappear, decrease arsenic trioxide and/or tretinoin to the previous dose

QTc Prolongation

  • QTc prolongation greater than 450 milliseconds (men) or greater than 460 milliseconds (women)
  • Withhold treatment and any medication known to cause QT prolongation
  • Replete electrolytes
  • After QTc normalizes, resume arsenic trioxide at a 50% reduced dose (0.075 mg/kg once daily) for 7 days
  • If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase the dose to 0.11 mg/kg once daily for 7 days
  • The dose can be increased to 0.15 mg/kg in the absence of QTc prolongation during that 14-day dose-escalation period

Hepatoxicity

  • Defined by 1 or more of the following: Total bilirubin (TB) greater than 3x ULN; AST greater than 5x ULN; alkaline phosphatase (AP) greater than5x ULN
  • Withhold treatment with arsenic trioxide and/or tretinoin
  • Resume treatment at a 50% reduced dose of the withheld drug(s) when TB is less than 1.5x ULN and AP/AST is less than 3x ULN
  • After 7 days on the reduced dose in the absence of worsening of hepatotoxicity; increase the dose of the withheld drug(s) back to the recommended dosage
  • Permanently discontinue the withheld drug(s) if hepatotoxicity recurs

Other severe or life-threatening (grade 3-4) nonhematologic reactions

  • Temporarily withhold arsenic trioxide and tretinoin
  • When adverse reaction resolves to up to grade 1, resume treatment reduced by 2 dose levels (see below)

Moderate (grade 2) nonhematologic reactions

  • Reduce the dose of arsenic trioxide and/or tretinoin by 1 dose level (see below)

Leukocytosis (WBC count greater than 10 Gi/L)

  • Administer hydroxyurea
  • Discontinue hydroxyurea when WBC is less than 10 Gi/L

Myelosuppression

  • Defined by 1 or more of the following: ANC less than1 Gi/L; platelets less than 50 Gi/L lasting more than 5 weeks
  • Consider reducing the dose of arsenic trioxide and tretinoin by following: 1 dose level (see below)
  • If myelosuppression lasts 50 days or more or occurs on 2 consecutive cycles, assess a marrow aspirate for remission weeks status
  • In the case of molecular remission, resume treatment at 1 dose level lower

Dosing reduction levels for hematologic and nonhematologic toxicities

  • Arsenic trioxide
    • Starting level: 0.15 mg/kg IV once daily
    • Level -1: 0.11 mg/kg IV once daily
    • Level -2: 0.1 mg/kg IV once daily
    • Level -3: 0.075 mg/kg IV once daily
  • Tretinoin
    • Starting level: 22.5 mg/m2 orally twice daily
    • Level -1: 18.75 mg/m2 orally twice daily
    • Level -2: 12.5 mg/m2 orally twice daily
    • Level -3: 10 mg/m2 orally twice daily

Renal impairment

  • Severe: (CrCl less than 30 mL/minute): Exposure of arsenic trioxide may be higher; monitor for toxicities and dose reduce when warranted
  • Dialysis: Safety and efficacy not established

Hepatic impairment

  • Limited data available for all hepatic impairment groups; use with caution
  • Severe (Child-Pugh C): Monitor for toxicities

What Are Side Effects Associated with Using Arsenic Trioxide?

Common side effects of Arsenic Trioxide include:

Less common side effects of arsenic trioxide include:

Postmarketing side effects of arsenic trioxide reported include:

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

What Other Drugs Interact with Arsenic Trioxide?

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

  • Severe interactions of arsenic trioxide include:
    • artemether/lumefantrine
    • cisapride
    • dronedarone
    • epinephrine racemic
    • erythromycin base
    • erythromycin ethylsuccinate
    • erythromycin lactobionate
    • erythromycin stearate
    • goserelin
    • leuprolide
    • nilotinib
    • octreotide (Antidote)
    • pimozide
    • trazodone
    • ziprasidone
  • Arsenic trioxide has serious interactions with 73 different drugs.
  • Arsenic trioxide has moderate interactions with 34 different drugs.
  • Arsenic trioxide has no listed mild interactions with other drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

What Are Warnings and Precautions for Arsenic Trioxide?

Warnings

  • This medication contains arsenic trioxide. Do not take Trisenox if you are allergic to arsenic trioxide or any ingredients contained in this drug.

Black Box Warnings

Differentiation syndrome

  • Differentiation syndrome was reported, 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 multi-organ 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

Cardiac conduction abnormalities

  • Can cause QTc interval prolongation, complete atrioventricular block, and torsade de pointes-type ventricular arrhythmia, which can be fatal
  • Before initiating therapy, assess the QTc interval, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong the QTc interval
  • Do not administer to patients with ventricular arrhythmia or prolonged QTc

Encephalopathy

  • Serious encephalopathy, including Wernicke’s, reported; Wernicke’s 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 therapy;
  • If encephalopathy is suspected, immediately interrupt therapy and initiate parenteral thiamine; monitor until symptoms resolve or improve and thiamine levels normalize

Contraindications

  • Hypersensitivity

Effects of Drug Abuse

  • No information is available.

Short-Term Effects

  • See "What Are Side Effects Associated with Using Arsenic Trioxide?"

Long-Term Effects

  • See "What Are Side Effects Associated with Using Arsenic Trioxide?"

Cautions

  • Use caution in hepatic or renal impairment
  • Arsenic trioxide is a human carcinogen; monitor patients for the development of second primary malignancies
  • Differentiation syndrome, which may be life-threatening or fatal, observed in patients with acute promyelocytic leukemia (APL) treated with the drug (16-23% of patients developed differentiation syndrome); the syndrome has been observed with and without concomitant hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as second-month induction therapy; when therapy is used in combination with tretinoin, prednisone prophylaxis is advised; at the first signs of differentiation syndrome, interrupt treatment and administer dexamethasone 10 mg intravenously twice daily; continue high-dose steroids until signs and symptoms have abated for at least 3 days
  • Prolongs QTc interval; for patients who develop a QTc greater than 500 milliseconds, immediately withhold treatment and any medication known to prolong the QTc interval; correct electrolyte abnormalities; when QTc normalizes, resume therapy at a reduced dose
  • In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with arsenic trioxide in combination with tretinoin experienced elevated AST, alkaline phosphatase, and/or serum bilirubin; long term liver abnormalities can occur in APL patients treated with arsenic trioxide in combination with tretinoin
  • Fetal harm may occur when administered to a pregnant woman

Encephalopathy

  • Wernicke’s encephalopathy reported in patients receiving therapy; Wernicke’s encephalopathy is a neurologic emergency that can be prevented and treated with thiamine
  • Consider testing thiamine levels in patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide)
  • Administer parenteral thiamine in patients with or at risk for thiamine deficiency; monitor patients for neurological symptoms and nutritional status while receiving therapy if Wernicke's encephalopathy is suspected, immediately interrupt therapy and initiate parenteral thiamine

Drug interactions overview

  • Coadministration with drugs that can prolong QT/QTc interval may increase the risk of serious QT/QTc interval prolongation
  • Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation
  • Coadministration with drugs that can lead to hepatotoxicity, particularly when given in combination with tretinoin, may increase the risk of serious hepatotoxicity

Pregnancy and Lactation

  • No studies with arsenic trioxide have been conducted in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on the mechanism of action and findings in animal studies, arsenic trioxide can cause fetal harm when administered to a pregnant woman.
  • Arsenic trioxide was embryo lethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on an mg/2 basis. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on an mg/2 basis and in hamsters at an IV dose approximately equivalent to the projected human daily dose on an mg/2 basis.
    • Females of reproductive potential should have a pregnancy test before initiation of treatment
    • Females of reproductive potential are advised to use effective contraception during and after treatment and for 6 months after the final dose
    • Based on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, arsenic trioxide may impair fertility in males of reproductive potential
  • Arsenic trioxide is excreted in milk. Because of the potential for serious adverse reactions in nursing infants from arsenic trioxide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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References
https://reference.medscape.com/drug/trisenox-arsenic-trioxide-342190