Arsenic Trioxide

Trade Names:Trisenox- Solution for injection 1 mg/mL in 10 mL ampules

Pharmacology

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.

Pharmacokinetics

Metabolism

Pentavalent arsenic is reduced to trivalent arsenic by arsenate reductase. Trivalent arsenic is methylated to monomethyl arsenic, which is then converted to dimethyl arsenic by methyltransferase. Methylation reactions are done in the liver.

Elimination

Excreted in the urine as methylated metabolite.

Indications and Usage

Refractory or relapsed acute promyelocytic leukemia (APL). Safety and efficacy in children younger than 5 yr of age not established.

Contraindications

Standard considerations.

Dosage and Administration

IV 0.15 mg/kg/day until bone marrow remission, do not exceed 60 doses.

IV 0.15 mg/kg/day for 25 doses over a period of up to 5 wk. Begin 3 to 6 wk following induction.

General Advice

• Withdraw the desired dose from the ampule, using aseptic technique.
• Use a filter needle and dilute with 100 to 250 mL dextrose 5% or sodium chloride 0.9% prior to administration.
• Diluted solutions are stable for 24 h at room temperature or 48 h if refrigerated.
• Discard the undiluted solution within 24 h of opening.
• IV infusion over 1 to 2 h. Increase the infusion time to 4 h if acute vasomotor reactions occur, such as dizziness, hypotension, tachycardia, or flushing.

Storage/Stability

Store at room temperature. Do not freeze.

Drug Interactions

May increase and decrease blood glucose levels, necessitating dosage adjustment of these drugs.

Risk of arrhythmias may increase when arsenic trioxide is given concomitantly with these medications.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Tachycardia (55%); QTc interval greater than 500 msec (38%); palpitations; other ECG abnormalities; torsades de pointes; edema (40%); chest pain; hypotension; flushing; hypertension.

CNS

Fatigue; fever; headache (approximately 60%); insomnia; rigors; paresthesia; anxiety; dizziness; depression; tremor; weakness; convulsion; somnolence.

Dermatologic

Dermatitis; pruritus; ecchymosis; dry skin; nonspecific erythema; increased sweating; pallor; facial edema; night sweats; petechiae; hyperpigmentation; nonspecific skin lesions; urticaria; local exfoliation; eyelid edema; injection site pain; erythema; edema (10% to 20%).

GI

Moderate potential for nausea and vomiting; abdominal pain (58%); diarrhea; constipation; decreased appetite; elevated ALT and AST; abdominal discomfort.

Genitourinary

Vaginal hemorrhage (21%); breakthrough bleeding (13%); fetal harm possible; bone marrow chromosome defects in pregnant mice and neural tube defects in pregnant hamsters.

Hematologic

Leukocytosis (50%); thrombocytopenia; anemia; neutropenia (nadir 14 to 21 days); hemorrhage; disseminated intravascular coagulation; lymphadenopathy.

Hypersensitivity

Rash (up to 5%).

Metabolic

Hypokalemia, hypomagnesemia, hyperglycemia (up to 15% to 50%); hyperkalemia; weight gain; hypocalcemia; hypoglycemia.

Musculoskeletal

Arthralgia; myalgia; bone pain; nonspecific back, neck, and limb pain.

Renal

Renal function impairment (up to 10%).

Respiratory

Cough; dyspnea; sore throat; epistaxis; hypoxia; pleural effusion; post nasal drip; wheezing; changes in breath sounds; hemoptysis; tachypnea.

Special Senses

Eye irritation, blurred vision, dry eyes, earache, tinnitus, painful red eyes (up to 10%).

Miscellaneous

Retinoic-acid acute promyelocytic leukemia (RA-APL) syndrome during induction in up to 31% characterized by fever, dyspnea, weight gain, radiographic pulmonary infiltrates, pleural or pericardial effusions. Mean time to diagnosis was 17 days after initiating treatment (range, 7 to 24 days).

Precautions

Pregnancy

Category D .

Lactation

Arsenic is excreted in human milk. Decide whether to discontinue breast-feeding or the drug, taking into account the importance of the drug to the mother.

Children

Safety and efficacy in children younger than 5 yr of age not studied.

Adjustment in renal insufficiency

Dosage reduction may be necessary in patients with renal function impairment; however, specific recommendations are not available. Use additional caution in these patients.

Extravasation risk

Arsenic trioxide is an irritant; mild injection site reactions have been reported (13%). Local irritation or phlebitis may occur. Refer to your institution specific protocol.

Hyperleukocytosis

Common (50%) during arsenic trioxide therapy. Patients with higher baseline WBC (3,900 cells/mm ³ vs 1,200 cells/mm ³ ) may be at greater risk for developing hyperleukocytosis.

Overdosage

Symptoms

Convulsions, muscle weakness, confusion.

Patient Information

• Review dosing schedule with patient (ie, Induction Regimen and Consolidation Regimen).
• Advise patient that medication will be prepared and administered by health care provider in a health care setting.
• Instruct patient to immediately inform health care provider if fever, weight gain, difficulty breathing, or shortness of breath occur.
• Advise patient that follow-up visits and laboratory tests will be required to monitor therapy and to keep appointments.

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