Drug/Small Molecule:
arsenic trioxide

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 10/25/2013

FDA Label for arsenic trioxide and PML, RARA

This label is on the FDA Biomarker List
Genetic testing required

Summary

The FDA-approved drug label for arsenic trioxide (Trisenox) contains information regarding indication of the drug in patients whose acute promyelocytic leukemia (APL) is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. The label also states that some patients treated with arsenic trioxide have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, which can be fatal, and high-dose steroids (dexamethasone 10 mg intravenously BID) should be immediately initiated at the first signs.

Annotation

Excerpt from the arsenic trioxide (Trisenox) drug label:

TRISENOX is 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. The response rate of other acute myelogenous leukemia subtypes to TRISENOX has not been examined.


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. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha.


Some patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Arsenic Trioxide drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • Leukemia
    • Indications & usage section, Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Long QT Syndrome
    • Boxed warning section, Warnings section, toxicity
    • source: FDA Label
  • Neoplasms
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Torsades de Pointes
    • Warnings section, Adverse reactions section
    • source: PHONT
  • PML
    • Boxed warning section, Indications & usage section, Warnings section, Clinical pharmacology section, Clinical studies section, Mechanism of action section, other
    • source: FDA Label
  • RARA
    • Boxed warning section, Indications & usage section, Warnings section, Clinical pharmacology section, Clinical studies section, Mechanism of action section, other
    • source: FDA Label

last updated 10/25/2013

European Medicines Agency (EMA) Label for arsenic trioxide and PML, RARA

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) contains pharmacogenetic information regarding the indication of arsenic trioxide in patients with APL characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RAR-alpha gene.

Annotation

Excerpt from the arsenic trioxide (Trisenox) EPAR:

Therapeutic indications TRISENOX is indicated for induction of remission and consolidation in adult patients with relapsed/refractory acute promyelocytic leukaemia (APL), characterised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha) gene. Previous treatment should have included a retinoid and chemotherapy. The response rate of other acute myelogenous leukaemia subtypes to TRISENOX has not been examined.

Mechanism of action: The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein Pro-Myelocytic Leukaemia/Retinoic Acid Receptor-alpha (PML/RAR alpha).

This information is highlighted in the following sections:
Therapeutic indications, Pharmacodynamic properties.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the arsenic trioxide EPAR.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.


PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Acide Arsenieux [French]
  • Anhydride Arsenieux [French]
  • Arseni Trioxydum
  • Arsenic Blanc [French]
  • Arsenic Oxide
  • Arsenic Oxidearsenous Trioxide
  • Arsenic Sesquioxide
  • Arsenic Trioxide [UN1561] [Poison]
  • Arsenic, White
  • Arsenicum Album
  • Arsenigen Saure [German]
  • Arsenious Acid
  • Arsenious Acid Anhydride
  • Arsenious Oxide
  • Arsenious Trioxide
  • Arsenous Acid
  • Arsenous Acid Anhydride
  • Arsenous Anhydride
  • Arsenous Oxide
  • Arsenous Oxide Anhydride
  • Arsentrioxide
  • Crude Arsenic
  • Di-Arsenic Trioxide
  • Diarsenic Trioxide
  • Diarsonic Trioxide
  • HSDB 419
  • Oxyde Arsenieux [ISO-French]
  • Poison Flour
  • White Arsenic
  • arsenic trioxide
Trade Names
  • Arsenite
  • Arsenolite
  • Arsodent
  • Claudelite
  • Claudetite
  • Trisenox
Brand Mixture Names

PharmGKB Accession Id:
PA448486

Description

Arsenic trioxide is a chemotheraputic agent of idiopathic function used to treat leukemia that is unresponsive to first line agents. It is suspected that arsenic trisulfide induces cancer cells to undergo apoptosis. Due to the toxic nature of arsenic, this drug carries significant health risks. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide.

Source: Drug Bank

Indication

For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis.

Source: Drug Bank

Pharmacology

Arsenic Trioxide is 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.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases. The main site of methylation reactions appears to be the liver. Arsenic is stored mainly in liver, kidney, heart, lung, hair and nails.

Source: Drug Bank

Protein Binding

75% bound

Source: Drug Bank

Toxicity

Symptoms of overdose include convulsions, muscle weakness and confusion.

Source: Drug Bank

Route of Elimination

Trivalent arsenic is mostly methylated in humans and excreted in urine.

Source: Drug Bank

Chemical Properties

Chemical Formula

As2O3

Source: Drug Bank

Isomeric SMILES

O=[As](=O)=O

Source: OpenEye

Canonical SMILES

O1[As]2O[As]

Source: Drug Bank

Average Molecular Weight

197.8414

Source: Drug Bank

Monoisotopic Molecular Weight

197.8279367

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Antiarrhythmic Pathway, Pharmacodynamics
    Pharmacodynamic pathway of antiarrhythmic drugs in a stylized cardiac myocyte.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
KCNH2
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
MT1A
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PML
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
RARA

Drug Targets

Gene Description
ABCB1 (source: Drug Bank)
AKT1 (source: Drug Bank)
ATP2C1 (source: Drug Bank)
CCND1 (source: Drug Bank)
ERGIC2 (source: Drug Bank)
IKBKB (source: Drug Bank)
IL6 (source: Drug Bank)
JUN (source: Drug Bank)
MAPK1 (source: Drug Bank)
MAPK3 (source: Drug Bank)
TXNRD1 (source: Drug Bank)
No related drugs are available.

Curated Information ?

Publications related to arsenic trioxide: 14

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The genetics of pro-arrhythmic adverse drug reactions. British journal of clinical pharmacology. 2014. Petropoulou Evmorfia, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomic characterization of US FDA-approved cytotoxic drugs. Pharmacogenomics. 2011. Peters Eric J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
KCNH2 pharmacogenomics summary. Pharmacogenetics and genomics. 2010. Oshiro Connie, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Drug-induced long QT syndrome. Pharmacological reviews. 2010. Kannankeril Prince, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica; the fate of foreign compounds in biological systems. 2008. Hagenbuch B, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008. Ito Keisuke, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Glutathione S-transferase omega 1 and omega 2 pharmacogenomics. Drug metabolism and disposition: the biological fate of chemicals. 2006. Mukherjee Baidehi, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies. The Journal of biological chemistry. 2006. Wood Thomas C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. The Journal of pharmacology and experimental therapeutics. 2006. Katchman Alexander N, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells. Journal of cellular physiology. 2005. Tabellini Giovanna, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Mechanisms of arsenic-induced prolongation of cardiac repolarization. Molecular pharmacology. 2004. Ficker Eckhard, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Arsenic trioxide inhibits p-glycoprotein expression in multidrug-resistant human leukemia cells that overexpress the MDR1 gene. Chinese medical journal. 2003. Wei Hulai, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
63459-600-10
DrugBank:
DB01169
KEGG Drug:
D02106
PubChem Compound:
518740
PubChem Substance:
10506726
46506448
Drugs Product Database (DPD):
718777
ChemSpider:
452539
Therapeutic Targets Database:
DNC000255
FDA Drug Label at DailyMed:
dec51fab-3784-deb7-752f-2d4d5692a20f

Clinical Trials

These are trials that mention arsenic trioxide and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.