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arsenic trioxide

( AR-se-nik tri-OX-ide )
Funding:
New Drug Funding Program
  • Arsenic Trioxide - First Line Consolidation of Acute Promyelocytic Leukemia (APL)
  • Arsenic Trioxide - First Line Induction of Acute Promyelocytic Leukemia (APL)
  • Arsenic Trioxide - Relapsed_Refractory Induction of Acute Promyelocytic Leukemia (APL)
  • Arsenic Trioxide - Relapsed_Refractory Consolidation of Acute Promyelocytic Leukemia (APL)
Other Name(s): Trisenox® (Lundbeck)
Appearance: clear, colourless solution mixed into larger bags of fluids
A - Drug Name

arsenic trioxide

SYNONYM(S):   As2O3

COMMON TRADE NAME(S):   Trisenox® (Lundbeck)

 
B - Mechanism of Action and Pharmacokinetics

 

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocations of the retinoic acid receptor alpha gene (RAR-α) on chromosome 17 and the promyelocytic leukemia gene (PML) on chromosome 15. The resulting fusion gene, PML–RAR-α , encodes a chimeric protein which causes an arrest of myeloid cell maturation at the promyelocyte stage of development.

The mechanism of action of arsenic trioxide is not completely understood but is likely multimodal.  At lower doses, arsenic promoted cellular differentiations, while apoptosis was noted at higher concentrations.

 

 
Absorption
Peak plasma levels2 hrs
BioavailabilitySystemic exposure (AUC) appears linear at 0.15 mg/kg.
Distribution

Widely distributed throughout tissues

PPBNegligible
Distribution SitesLiver, kidney and heart; to a lesser extent in lung, hair and nails.  No evidence of distribution in adipose tissues.
Cross blood brain barrier?Yes
Metabolism

Methylation in the liver to less cytotoxic metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV). Oxidation of AsIII to AsV (low plasma levels) in many tissues via enzymatic or nonenzymatic processes. 

Active metabolitesAsIII (primary), possibly other trivalent and pentavalent methylated metabolites
Inactive metabolitesYes
Elimination
Urine15% unchanged AsIII; 10 - 20% MMA; 60 - 70% DMA.
ClearanceA 45% reduction in total clearance of AsIII is noted with multiple dosing which may contribute to accumulation.  Clearance is not dependent on body weight or dose administered at 0.15 mg/kg.
Half-life10 - 14 hours (AsIII), 32 hours for MMAV and 70 hours for DMAV
 
C - Indications and Status
Health Canada Approvals:

Induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), which is refractory to or has relapsed from retinoid and anthracycline therapy, and whose APL is characterized by the presence of the t(15;17) translocation or promyelocytic leukemia-retinoic-acid-receptor alpha (PML-RARα) gene expression.
 
 
D - Adverse Effects

Emetogenic Potential:  

Moderate

 

Extravasation Potential:   None

ORGAN SITESIDE EFFECT* (%)ONSET**
AuditoryEar pain (8%)E
 Tinnitus (5%)E
CardiovascularArrhythmia (5%) (including complete AV block, sudden death)I
 Cardiotoxicity (rare)E  D
 Flushing (10%)I  E
 Hypertension (10%)I  E
 Hypotension (25%)I  E
 QT interval prolonged (33%) (3% severe)I
 Tachycardia (55%) (mild to moderate)I
 Venous thromboembolism (<5%)E
DermatologicalRash (45%) (may be severe)E
 Skin hyperpigmentation (8%)E
GastrointestinalAbdominal pain (38%)E
 Anorexia (38%)E
 Constipation (28%)E
 Diarrhea (63%)E
 Dyspepsia (10%)I  E
 Nausea, vomiting (75%)I
GeneralEdema (45%) (may be severe)E
 Fatigue (68%)E
HematologicalDisseminated intravascular coagulation (8%)E  D
 HyperleukocytosisE
 Myelosuppression ± infection, bleeding (13%) (severe)E
 Other (23%) (APL differentiation syndrome)E
Hepatobiliary↑ LFTs (23%) (8% severe)E
HypersensitivityHypersensitivity (5%) (3% severe)I
Injection siteInjection site reaction (23%)I  E
Metabolic / EndocrineAbnormal electrolyte(s) (50%) (↑/↓Mg, ↑/↓K, ↓Ca, ↓PO4; 13% severe)E
 Hyperglycemia (45%) (severe 13%)E
 Tumor lysis syndrome (rare)I
MusculoskeletalMusculoskeletal pain (33%) (severe 8%)E
Nervous SystemAnxiety (33%)E
 Depression (20%)E  D
 Dizziness (25%)E
 Headache (63%)E
 Insomnia (43%)E
 Paresthesia (33%) (5% severe)E
 Seizure (8%)E
 Somnolence (8%)E
OphthalmicBlurred vision (10%)E
 Conjunctivitis (10%)E
RenalProteinuria (5%)E
 Renal failure (8%)E  D
RespiratoryCough, dyspnea (65%) (severe 10%)E
 Pneumonitis (<5%)E
VascularVasculitis (<5%)E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for arsenic trioxide include nausea/vomiting , fatigue, cough/dyspnea, diarrhea, headache, tachycardia, abnormal electrolyte(s), leukocytosis, edema and hyperglycemia.

Since arsenic trioxide induces partial differentiation of APL cells, hyperleukocytosis may occur in some patients, but does not appear to be related to baseline white blood cell counts.  Hyperleukocytosis usually resolved without additional chemotherapy treatment. 

Life-threatening APL differentiation syndrome has been observed in some patients.  Patients may present with dyspnea, unexplained fever, weight gain, peripheral edema, hypotension, acute renal failure, congestive heart failure and pulmonary infiltrates.  Administer high-dose steroids (e.g. dexamethasone 10 mg BID) at the first signs of APL syndrome, irrespective of the leukocyte count, and continue for at least 3 days or longer until resolution.  Hold arsenic trioxide treatment for patients who develop severe APL differentiation syndrome. 

Most cases of elevated transaminases have been reported to resolve without interruption of treatment. 

Although most cases of peripheral neuropathy are mild and moderate,  some may be severe and/or irreversible.

 

 
E - Dosing
 

Refer to protocol by which patient is being treated. Numerous dosing schedules exist depending on disease, response and concomitant therapy.


 
Adults:
 
  • Do not start treatment in patients with QT/QTc > 500 msec.  Correct electrolyte abnormalities and start only if QT <430 msec for males or <450 msec for females.
  • During treatment with arsenic trioxide, potassium concentration should be kept > 4 mmol/L and magnesium concentrations should be kept > 0.74 mmol/L.
  • Do not exceed the maximum number of doses recommended for the induction and consolidation treatments.
  • Obese patients should be dosed based on lean weight.
For induction treatment:
Intravenous: 0.15 mg/kg/day until bone marrow remission. Total induction dose should not exceed 60 doses.
 
For consolidation treatment:
Intravenous: 0.15 mg/kg/day for 25 doses over a period up to 5 weeks, starting 3 to 6 weeks after completion of induction therapy
 
Dosage with Toxicity:
 
Toxicity while on treatmentAction
QT/QTc > 500 msecHold; investigate and correct risk factors.  May start if QTc < 430 msec for males and < 450 msec for females.
Syncope, rapid heart rate or arrhythmiaHold. Monitor and correct electrolyte abnormalities. Restart when QT < 460 msec and syncope and arrhythmia resolve.
K ≤ 4mmol/L and/or Mg ≤ 0.74  mmol/LHold. Monitor and correct electrolyte abnormalities. Restart if Mg and K recover and no signs of arrhythmia.
Signs and symptoms of APL differentiation syndromeStart high-dose steroids (e.g. dexamethasone 10mg IV BID) for ≥ 3 days until resolution of signs and symptoms.  Hold arsenic trioxide for severe signs and symptoms.
Other grade 3 related non-hematological toxicityHold. Restart if recovered to baseline with a 50% dose reduction.  If toxicity does not recur within 3 days, ↑ to previous dose.  Discontinue if recurs.

Other grade 4 related
non-hematological toxicity

Discontinue
OR
Hold. Restart if recovered to baseline with a 50% dose reduction.  If toxicity does not recur within 3 days, ↑ to previous dose.  Discontinue if recurs.

Overdose:  Symptoms suggesting severe acute arsenic toxicity may include convulsions, muscle weakness and confusion.  Discontinue drug, monitor ECG and consider chelation therapy.  A suggested protocol for acute arsenic intoxication includes dimercaprol 3 mg/kg IM q4h until resolution of immediate life-threatening toxicity.


 
Dosage with Hepatic Impairment:
 

No clear increase in systemic exposure to arsenic trioxide or its metabolites with mild or moderate hepatic function was observed; dosage adjustment is likely not needed in mild to moderate liver impairment.  Plasma metabolite levels may be increased in severe hepatic impairment; dose reduction should be considered in severe hepatic impairment (Child-Pugh C).

Hepatic impairment

Recommended dose

Mild (Child Pugh A)

0.15 mg/kg/day

Moderate (Child Pugh B)

0.15 mg/kg/day

Severe (Child Pugh C)

Consider decrease


 
Dosage with Renal Impairment:
 

Based on limited data, dosage adjustment is likely not needed in mild to moderate renal impairment.  Dose reduction should be considered in severe renal impairment (CrCl < 30 mL/min) due to increased exposure and/or decreased clearance of metabolites.  The use of arsenic trioxide in dialysis patients has not been studied.

Renal impairment

Recommended dose

Mild (CrCl 50 - 80 mL/min)

0.15 mg/kg/day

Moderate (CrCl 30 - 49 mL/min)

0.15 mg/kg/day

Severe (CrCl < 30 mL/min)

Consider decrease


 
Dosage in the elderly:
 

Limited data available; use with caution.


 
Dosage based on gender:
 

No information available.


 
Dosage based on ethnicity:
 

No information available.


 
Children:
 

There are no data for children < 5 years of age.  Data is limited in pediatric patients (aged >5 to <18 years).  Exposure is expected to be > 50% higher than that in adults; monitor patients closely.  Obese pediatric patients should be dosed based on ideal body weight. 


 
 
F - Administration Guidelines
  • Dilute dose with 100-250 mL of dextrose 5% injection or Normal Saline.
  • Administer IV over 1-2 hours.  The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. 
  • A central venous catheter is not required.
  • Do not administer in the same IV line or admix with other drugs.
  • Store unopened ampoules at 15-30°C.  Do not freeze. 
 
G - Special Precautions
Contraindications:

 

  • patients who have a hypersensitivity to this drug or any of its components

     

  • patients with QT/QTc interval > 500 msec

     

     

 

Other Warnings/Precautions:

 

  • Avoid concurrent use of drugs that prolong the QT interval or disrupt electrolyte levels. Pre-existing electrolyte abnormalities must be corrected before treatment with arsenic trioxide.
  • Exercise caution in patients with increased QT interval or who are at risk (e.g. age > 65 years, low potassium/magnesium, congenital or pre-existing QT prolongation, CHF, prior anthracycline, diabetes, autonomic neuropathy).
  • Exercise caution in patients with conditions that may be exacerbated by an increase in heart rate, such as tachyarrhythmias or ischemic heart disease.  Patients with syncope, rapid or irregular heartbeat should be hospitalized for monitoring.
  • Exercise caution in patients with renal impairment, as this may result in overdose levels of the drug and may be fatal.
  • Obese patients may experience higher than expected plasma and tissue concentrations of arsenical species.

     

  • Poor nutritional status may decrease the capacity to methylate and detoxify arsenic.  Decreased glutathione levels increase arsenic concentration and toxicity.

     

     

 


Other Drug Properties:

 

  • Carcinogenicity: Yes
    (observed with arsenic)

 

Pregnancy and Lactation:
  • Embryotoxicity: Yes
    Arsenic crosses the placental barrier.
  • Teratogenicity: Yes
    Arsenic trioxide is contraindicated in pregnancy.  Adequate contraception must be used by both sexes during treatment with arsenic trioxide and for 3 months after the last dose.
  • Genotoxicity: Yes
    (weak)
  • Clastogenicity: Yes
  • Lactation: Contraindicated
    Arsenic is excreted in human milk; breastfeeding is contraindicated during arsenic trioxide treatment and for 3 months after the last dose.
  • Fertility effects: Yes
 
H - Interactions

 

AGENTEFFECTMECHANISMMANAGEMENT
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc)↑ risk of QT prolongationAdditiveDiscontinue during treatment with arsenic trioxide
Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids)↑ risk of arrhythmiasAdditiveAvoid
Previous anthracycline use↑ risk of QT prolongationCardiotoxic effectsCaution
Strong Pgp or MRP inhibitors↑ arsenic exposure and/or toxicity↓ efflux of arsenic trioxideCaution
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors)↓ substrate concentration and/or efficacy↑ metabolism of CYP3A4 substratesCaution, especially substrates with narrow therapeutic range
CYP2A substrates↓ substrate concentration and/or efficacy↑ metabolism of CYP2A substratesCaution, especially substrates with narrow therapeutic range
CYP2B1/2 substrates↓ substrate concentration and/or efficacy↑ metabolism of CYP2B1/2 substratesCaution, especially substrates with narrow therapeutic range
 
I - Recommended Clinical Monitoring

Hospitalize patients with syncope or tachyarrhythmia

Recommended Clinical Monitoring
 
Monitor TypeMonitor Frequency
ECG; at baseline, twice weekly and more frequently as clinically indicated.  (Consider continuous ECG monitoring for patients with risk factors for QT prolongation/torsade de pointes.) 
Electrolytes (including magnesium and calcium)At baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
Liver and renal function testsAt baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
CBCAt baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
Blood glucose levelsAt baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
PT/INRAt baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
Clinical toxicity assessment for APL differential syndrome, QT prolongation/arrhythmias, tumour lysis syndrome, ↑LFTs, pulmonary infiltrates/effusionBaseline and regular

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
 
 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Arsenic Trioxide - First Line Consolidation of Acute Promyelocytic Leukemia (APL)
  • Arsenic Trioxide - First Line Induction of Acute Promyelocytic Leukemia (APL)
  • Arsenic Trioxide - Relapsed_Refractory Induction of Acute Promyelocytic Leukemia (APL)
  • Arsenic Trioxide - Relapsed_Refractory Consolidation of Acute Promyelocytic Leukemia (APL)

 

 
K - References

 

Prescribing Information:  Trisenox (arsenic trioxide).  Cephalon (US) Inc., June 2010.

Product Monograph:  Trisenox® (arsenic trioxide).  Lundbeck Canada Inc., June 6, 2013.

Soignet SL, Frankel SR, Douer D, et al.  United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia.  J Clin Oncol 2001;19(18):3852-60.

Soignet SL, Maslak P, Wang ZG, et al.  Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide.  N Engl J Med 1998;339(19):1341-8.

Summary of Product Characteristics:  Trisenox (arsenic trioxide).  Cephalon (UK) Ltd., January 28, 2013.

 

 

October 2017 Removed hyperlinks to NDFP forms

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

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