Drug information of Arsenic trioxide

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Arsenic trioxide

فارسی

Arsenic trioxide is a chemotheraputic agent of idiopathic function used to treat leukemia that is unresponsive to first line agents.

Mechanism of effect

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.

Pharmacokinetics

Peak plasma time: 2 hr (arsenious acid [AsIII])

Peak plasma time, after first administration: ~10-24 hr (Monomethylarsonic acid [MMA], and dimethylarsinic acid [DMA])

AUC (Cycle 1, Day 1): 194 ng·hr/mL (arsenious acid)

AUC (Cycle 1, Day 25): 332 ng·hr/mL (arsenious acid)

Vd (steady-state): 562 L

Metabolism:

Arsenious acid is distributed to the tissues it methylate to the metabolites, MMA and DMA by methyltransferases primarily in the liver

Metabolism of arsenic trioxide also involves oxidation of AsIII to AsV, which may occur in numerous tissues via enzymatic or nonenzymatic processes

Clearance, AsIII: 49 L/h (total); 9 L/hr (renal)

Half-life: 32 hr (MMA); 72 hr (DMA)

Dosage

Adult

Acute Promyelocytic Leukemia

Newly diagnosed low-risk acute promyelocytic leukemia (APL)

  • Treatment course consists of 1 induction and 4 consolidation cycles
  • Induction cycle
    • Arsenic trioxide 0.15 mg/kg IV qDay until bone marrow remission; not to exceed 60 days, PLUS 
    • Tretinoin 22.5 mg/m² PO BID 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 PO BID 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

  • Treatment course consists of 1 induction and 1 consolidation cycle
  • Induction cycle
    • Arsenic trioxide 0.15 mg/kg IV qDay 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 over a period of up to 5 weeks 

Pediatric

Acute Promyelocytic Leukemia

Refractory or relapse after retinoid and anthracycline chemotherapy

  • <4 years: Safety and efficacy not established
  • ≥4 years: 0.15 mg/kg IV qDay until bone marrow remission; not to exceed 60 doses 
  • Wait 3-6 weeks, THEN
  • 0.15 mg/kg IV qDay for 25 doses (administered over time period of up to 5 weeks)

Alerts

Use caution in hepatic or renal impairment

Arsenic trioxide is a human carcinogen; monitor patients for development of second primary malignancies

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 (do Dosage Modifications)

Black Box Warnings

Differentiation syndrome

  • Differentiation syndrome 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 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 QTc interval
  • Do not administer to patients with ventricular arrhythmia or prolonged QTc

Points of recommendation

Both men and women using arsenic trioxide should use effective birth control to prevent pregnancy. Arsenic trioxide can harm an unborn baby or cause birth defects if the mother or father is using this medicine.

  • If you are a woman, keep using birth control for at least 6 months after your last dose.
  • If you are a man, keep using birth control for at least 3 months after your last dose.

This medicine may affect fertility (ability to have children) in men. However, it is important to use birth control to prevent pregnancy because arsenic trioxide may harm the baby if a pregnancy does occur.

It is not safe to breast-feed a baby while you are using this medicine. Also do not breast-feed for at least 2 weeks after your last dose.

arsenic trioxide can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Wash soiled clothing and linens separately from other laundry.

Drug contraindications

Hypersensitivity

Pregnancy level

X

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