pharmacopeia
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/api/v1/drug/arsenic-trioxide

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DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKE'S Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with TRISENOX have experienced differentiation syndrome, which may be life-threatening or fatal. Signs and symptoms may include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy, and multi-organ dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold TRISENOX [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 )]. Cardiac Conduction Abnormalities: TRISENOX can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering TRISENOX, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with a ventricular arrhythmia or prolonged QTc interval. Withhold TRISENOX until resolution and resume at reduced dose for QTc prolongation [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 )].

Mechanism of action

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The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro.

Indications

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  • TRISENOX is an arsenical indicated: In combination with tretinoin for 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 PML/RAR-alpha gene expression. ( 1.1 ) 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.ICD-10: C95.90

Contraindications

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  • TRISENOX is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic.contraindicated

Dosage & administration

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Newly-diagnosed low-risk APL: Induction: Administer 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission. Do not exceed 60 days. ( 2.1 ) Consolidation: Administer 0.15 mg/kg/day intravenously daily for 5 days per week during weeks 1-4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin. ( 2.1 ) Relapsed or refractory APL: Induction: Administer 0.15 mg/kg/day intravenously daily until bone marrow remission. Do not exceed 60 days. ( 2.2 ) Consolidation: Administer 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. ( 2.2 ) 2.1 Recommended Dosage for Newly-Diagnosed Low-Risk Acute Promyelocytic Leukemia (APL) A treatment course for patients with newly-diagnosed low-risk APL consists of 1 induction cycle and 4 consolidation cycles. For the induction cycle, the recommended dosage of TRISENOX is 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission but not to exceed 60 days (see Table 1). For the consolidation cycles, the recommended dosage of TRISENOX is 0.15 mg/kg/day intravenously daily 5 days per week during weeks 1-4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin (see Table 1). Omit tretinoin during weeks 5-6 of the fourth cycle of consolidation.

Warnings & precautions

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Hepatotoxicity : Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold TRISENOX for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution.( 2.3 , 5.4 ) Carcinogenesis : Arsenic trioxide is a human carcinogen. Monitor patients for the development of second primary malignancies. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Differentiation Syndrome Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with TRISENOX. In clinical trials, 16-23% of patients treated with TRISENOX for APL developed differentiation syndrome. Signs and symptoms include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction. Differentiation syndrome has been observed with and without concomitant leukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy.

Adverse reactions

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The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] Cardiac Conduction Abnormalities [see Warnings and Precautions ( 5.2 )] Encephalopathy [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Carcinogenesis [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (> 30%) are 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 ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly-Diagnosed Low-Risk APL The safety of TRISENOX in combination with tretinoin was evaluated in Study APL0406, a randomized trial comparing TRISENOX plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL [see Clinical Studies ( 14.1 )] . In the TRISENOX/tretinoin group, 98% of patients completed induction therapy and 89% completed at least three consolidation cycles.

Use in specific populations

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Lactation : Advise not to breastfeed. ( 8.2 ) Renal Impairment : Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with TRISENOX; dose reduction may be warranted. ( 8.6 ) Hepatic Impairment : Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with TRISENOX. ( 8.7 ) 8.1 Pregnancy Risk Summary Based on the mechanism of action [see Clinical Pharmacology ( 12.1 )] and findings in animal studies, TRISENOX can cause fetal harm when administered to a pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/m 2 basis (see Data) . 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 a mg/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 basis. There are no studies with the use of TRISENOX 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. Advise pregnant women of the potential risk to a fetus.

Pharmacokinetics

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Metabolism
The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As III ). As III is the pharmacologically active species of arsenic trioxide.

Overdosage

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Manifestations Manifestations of TRISENOX (arsenic trioxide) overdosage include convulsions, muscle weakness, and confusion. Management For symptoms of TRISENOX (arsenic trioxide) overdosage, immediately discontinue TRISENOX and consider chelation therapy. A conventional protocol for acute arsenic intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided. Thereafter, penicillamine at a dose of 250 mg orally, up to a maximum frequency of four times per day (≤ 1 g per day), may be given.

Approval history

Sourced from openFDA
  • Sep 25, 2000NDANDA021248Cephalon
  • Aug 31, 2018ANDAANDA208231Fresenius Kabi Usa
  • Nov 13, 2018ANDAANDA206228Zydus Pharms
  • Nov 13, 2018ANDAANDA210802Amring Pharms
  • Nov 15, 2018ANDAANDA209315Ingenus Pharms Llc
  • Nov 15, 2018ANDAANDA209780Nexus
  • Jan 25, 2021ANDAANDA210739Amneal
  • Oct 7, 2021ANDAANDA215059Gland

FDA shortages

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Reference statistics from the openFDA drug-shortage dataset. For a live view, consult the FDA database directly. Not clinical guidance.

  • Arsenic Trioxide, Injection, 1 mg/1 mL (NDC 50742-438-10)To be discontinued
    Sponsor: Ingenus Pharmaceuticals LLC
    Updated

FAERS reports

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Reference statistics only. FAERS reports are voluntarily submitted and are not incidence rates, safety signals, or causal evidence. Counts reflect reporting volume — how often a reaction was reported, not how often it occurs. For decision-grade use, consult openFDA and the FAERS Public Dashboard directly.
5,060 total reports matchedLatest report Share = reports listing the reaction ÷ total matched reports. Rows can sum to >100% because a single report often lists multiple reactions.
  1. 1Fatigue2955.8%
  2. 2Nausea2805.5%
  3. 3Electrocardiogram Qt Prolonged2635.2%
  4. 4Diarrhoea2424.8%
  5. 5Headache2364.7%
  6. 6Off Label Use2304.5%
  7. 7Pain2224.4%
  8. 8Dyspnoea2214.4%
  9. 9Differentiation Syndrome2144.2%
  10. 10Drug Ineffective2134.2%
  11. 11Pyrexia1933.8%
  12. 12Dizziness1893.7%
  13. 13Arthralgia1773.5%
  14. 14Vomiting1693.3%
  15. 15Asthenia1673.3%

Literature

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Recent PubMed references pinned to Arsenic Trioxide as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

Clinical trials

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The 10 most recently updated of 155 ClinicalTrials.gov registrations naming Arsenic Trioxide as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

Frequently asked questions

How does Arsenic Trioxide work?
The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro.
What is Arsenic Trioxide used for?
According to FDA labeling, Arsenic Trioxide carries indications including: TRISENOX is an arsenical indicated: In combination with tretinoin for 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 PML/RAR-alpha gene expression. ( 1.1 ) 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.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.
What class of drug is Arsenic Trioxide?
Arsenic Trioxide is classified as Other antineoplastic agents, Unknown Cellular or Molecular Interaction, Decreased DNA Integrity.
What are the brand names for Arsenic Trioxide?
Arsenic Trioxide is marketed under brand names including Trisenox.
What are the contraindications for Arsenic Trioxide?
Arsenic Trioxide labeling lists contraindications including: TRISENOX is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic.. Always consult the full prescribing information and a clinician.
Note. Data for arsenic-trioxide is illustrative MVP content compiled from public sources. pharmacopeia is for educational and informational use only and is not a substitute for professional medical advice.

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