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Drug Monographs
Treatment Regimens
Scientific Name:
ARSENIC TRIOXIDE
Brand Name(s):
Trisenox®

Drug Monograph

Pharmacology

Mechanism of Action

The mechanism of arsenic trioxide is not completely understood. It causes morphological changes and DNA fragmantation characteristics of apoptosis in NB4 human promyelocytic leukemia cells in vitro. It also causes damage or degradation of the fusion protein PML-RAR alpha.

Pharmacokinetics

Distribution:
stored mainly in liver, kidney, heart, lung, hair and nails
Excretion in breast-milk unknown.
cross blood brain barrier?  unknown.
Metabolism:
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 main site of methylation reactions appears to be the liver
Excretion:
Disposition of arsenic following intraveneous administration has not been studied. Trivalent arsenic is mostly methylated in humans and excreted in urine.

Side Effects

IMMEDIATE ONSET (hours to days)  
* tachycardia (55%), chest pain (25%)
    abnormal ECG results (38%)
   dyspnea (53%)
    nausea (75%) and vomiting (58%)
   rigors (38%)
EARLY ONSET
(days to weeks)
* pleural effusion (20%), cough (65%)
* leucocytosis (50%), OR thrombocytopenia (19%), anemia (14%),
neutropenia (10%)
   pyrexia (63%), fatique (63%),  abdominal pain (58%), parasthesia (33%),
    pruritus (33%), arthralgia (33%), myalgia (25%)
   anxiety (30%), anorexia (23%), depression (20%)
   insomnia (43%), dizziness (23%),
weakness (10%)
    bone pain (23%), injection site pain (20%)
   abnormal blood chemistry- hypokalemia (50%), hypomagnesia (45%), hyperglycemia (45%), hypocalcemia (10%)
    hypotension (25%) OR hypertension (10%)
   hypoxia (23%)
   elevated hepatic enzymes- ALT (20%), AST (13%)
   epistaxis (25%), sinusitis (20%), ecchymosis (20%)
DELAYED/LATE ONSET
(weeks to years)
   dermatitis (43%), dry skin (13%)
Many other adverse effects with reduced frequency are reported

Therapeutics

Approved Indications

OTHER ONCOLOGY USES (Not Approved in Canada)
• Acute Promyelocytic Leukemia- salvage
U.S. Indication: 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

Routes

Intraveneous

Administration

Dilute in 100-250mL bag (5% dextrose, normal saline); infuse over 1-2 hours (up to 4 hours if acute vasomotor reactions).

IV Compatibility

Normal saline, dextrose 5%

Dosing

Induction:
• 0.15 mg/kg daily until bone marrow remission (total induction should not exceed 60 doses)

Consolidation:
• 0.15 mg/kg daily for 25 doses over a period up to 5 weeks (should begin 3 to 6 weeks after completion of induction)

Antiemetic Risk

INTERMEDIATE RISK (10-30% of patients)
• Use a  dexamethasone pre-chemotherapy OR a dopamine receptor antagonist PRN post-chemotherapy  

Contraindications

Patients who are hypersensitive to arsenic.

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets  (CBC), serum electrolytes, and coagulation profiles before each cycle of treatment and twice weekly during induction treatment or weekly during consolidation treatment
• ECG tests weekly during induction and consolidation treatment

SUGGESTED CRITERIA
• Baseline & periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels (serum proteins may be added if indicated)]
• Baseline & periodic serum glucose levels

Extravasation Hazard

Not a vesicant

Significant Interactions

No formal assessments of pharmacokinetic drug-drug interactions between arsenic trioxide and other drugs have been conducted. Caution is advised when it is coadministered with other medication that can prolong the QT interval or lead to electrolyte abnormalities.

Product Information

Commercial Product Description

Brand Name: Trisenox Vial with 10 mg/10 mL (1 mg/mL).

Pharmaceutical Considerations

Injection:
One vial (10mL) contains of Arsenic trioxide solution (1mg/mL), sodium hydroxide, hydrochloric acid and water for injections; preservative-free; store at 25(C, excursions permitted to 15-30(C; do not freeze

Preparation:
Use proper aseptic techniques, immediately after withdrawal from the ampule; the ampule is a single-use, unused portions of each ampule should be discarded properly; do not save unused portions for later administration; do not mix with other medication

Diluted solution for infusion:
Compatible with D5W and NS. It is recommended that the dose be diluted in 100 to 250 mL and stated that, because it is prevervative-free, the diluted solution be used within 24 hours if stored at room temperature or 48 hours if refrigerated.

Handling Risk Level

Carcinogen 1KNOWN HAZARDOUS DRUG
IARC Carcinogen Risk Group 1 (Known Carcinogen)

  • This drug must be handled using precautions outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 1
IARC Carcinogen Risk Group 1 (Known Carcinogen)
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

NOTE:
EMERGING INFORMATION
This drug is under investigation and has not been widely used in oncology practice.  As new information is discovered, portions of this monograph may become outdated.  Refer to primary literature and revisions to official product monograph to ensure that information on this drug is current.

GUIDELINES:
Acute Promyelocytic Leukemia
pCODR Recommendation:  Arsenic trioxide (ATO) in combination with all trans-retinoic acid (ATRA) as first line treatment for the induction of remission and/or consolidation of low to intemediate risk APL and as consoidation treatment for high risk APL after induction with ATRA plus chemotherapy for patients with the t(15:17) translocation and/or PML/RAR-alpha gene expression. February 18, 2014

pCODR Recommendation:  Arsenic trioxide (ATO) as a treatment for the induction of remission and consolidation in pateints with APL who have relapsed after completion of first-line therapy, including ATO based regimens, or who have disease refractory to non-ATP based regimens, for patients with the t(15:17) translocation and/or PML/RAR-alpha gene expression. February 18, 2014

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on Arsenic Trioxide for APL.
• Go to "Additional Information" tab (above) for links to pCODR Reviews

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Specialized Level • Capital Health Only • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Non-Formulary • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.

New Cancer Drug Fund Status (Nova Scotia)

New Cancer Drug Fund (NCDF) funding approved for: Acute Promyelocytic Leukemia • Initial Therapy – In combination with all trans-retinoic acid (ATRA) in the first line setting as a treatment for the induction of remission and /or consolidation of low to intermediate risk APLand as a consolidation treatment for high risk APL after induction with ATRA plus chemotherapy for patients with the t(15;17) translocation and PML/RAR-alpha gene expression. • Relapsed/Refractory/Retreatment Therapy –.As a treatment for the induction of remission and consolidation in patients with APL who have relapsed after completion of first line therapy including ATO based regimens or who have disease refractory to non-ATO based regimens for patients with the t(15;17) translocation and PML/RAR-alpha gene expression. • Pediatric Patient Population-As a treatment for the pediatric APL population as described above in the initial and relapsed/refractory/retreatment therapy criteria.