Trisenox


arsenic trioxide

Trisenox

Pharmacologic class: Nonmetallic element, white arsenic

Therapeutic class: Antineoplastic

Pregnancy risk category D

FDA Box Warning

• Give under supervision of physician experienced in managing patients with acute leukemia.

• Some patients with acute promyelocytic leukemia (APL) treated with drug have had symptoms similar to retinoic-acid-acute promyelocytic leukemia (RA-APL) or APL differentiation syndrome, marked by fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions. Syndrome can be fatal; at first sign, give high-dose steroids immediately, regardless of patient's white blood cell count; continue steroids for at least 3 days or longer until signs and symptoms abate. Most patients don't require arsenic trioxide termination during treatment of APL differentiation syndrome.

• Drug may prolong QT interval and cause complete atrioventricular block. QT prolongation can lead to torsades de pointes-type ventricular arrhythmia, which can be fatal.

• Before starting therapy, obtain 12-lead ECG and assess serum electrolyte (potassium, calcium, and magnesium) and creatinine levels. Correct electrolyte abnormalities and, if possible, discontinue drugs known to cause QT prolongation. During therapy, maintain potassium level above 4 mEq/L and magnesium level above 1.8 mg/dL. If patient reaches absolute QT interval value above 500 msec, reassess and take immediate action to correct concomitant risk factors.

Action

Unclear. May cause morphologic changes and DNA fragmentation in promyelocytic leukemia cells, causing cell death and degradation of or damage to PML/RAR alpha (a fusion protein).

Availability

Injection: 1 mg/ml

Indications and dosages

➣ APL in patients who have relapsed or are refractory to retinoid and anthracycline chemotherapy

Adults and children ages 5 and older: Induction phase-0.15 mg/kg I.V. daily until bone marrow remission occurs, to a maximum of 60 doses. Consolidation phase-0.15 mg/kg I.V. daily for 25 doses over 5 weeks, starting 3 to 6 weeks after completion of induction phase.

Contraindications

• Hypersensitivity to drug

• Pregnancy

Precautions

Use cautiously in:

• renal impairment, cardiac abnormalities

• elderly patients

• breastfeeding patients

• children.

Administration

See Know that drug is carcinogenic. Follow facility policy for preparing and handling antineoplastics.

• Dilute in 100 to 250 ml of dextrose 5% in water or normal saline solution.

• Don't mix with other drugs.

• Infuse over 1 to 2 hours (may infuse over 4 hours if patient has vasomotor reaction).

Adverse reactions

CNS: headache, insomnia, paresthesia, dizziness, tremor, drowsiness, anxiety, confusion, agitation, rigors, weakness, seizures, coma

CV: ECG abnormalities, palpitations, chest pain, hypotension, hypertension, tachycardia, prolonged QT interval, torsades de pointes

EENT: blurred vision, painful red eye, dry eyes, eye irritation, swollen eyelids, tinnitus, earache, nasopharyngitis, postnasal drip, epistaxis, sinusitis, sore throat

GI: nausea, vomiting, constipation, diarrhea, abdominal pain, fecal incontinence, dyspepsia, dry mouth, mouth blisters, oral candidiasis, anorexia, GI hemorrhage

GU: urinary incontinence, intermenstrual bleeding, renal impairment, oliguria, renal failure, vaginal hemorrhage

Hematologic: anemia, lymphadenopathy, leukocytosis, thrombocytopenia, neutropenia, disseminated intravascular coagulation, hemorrhage

Metabolic: hypokalemia, hypomagnesemia, hyperglycemia, acidosis, hypoglycemia, hyperkalemia Musculoskeletal: joint, muscle, bone, back, neck, or limb pain

Respiratory: dyspnea, cough, hypoxia, wheezing, crackles, tachypnea, decreased breath sounds, crepitation, hemoptysis, rhonchi, upper respiratory tract infection, pleural effusion

Skin: flushing, erythema, pallor, bruising, petechiae, pruritus, dermatitis, dry skin, hyperpigmentation, urticaria, skin lesions, herpes simplex infection, local exfoliation, diaphoresis, night sweats

Other: fever, facial edema, weight gain or loss, bacterial infection, pain and edema at injection site, hypersensitivity reaction, sepsis

Interactions

Drug-drug. Drugs that can cause electrolyte abnormalities (such as amphotericin B, diuretics): increased risk of electrolyte abnormalities

Drugs that can prolong QT interval (antiarrhythmics, thioridazines, some quinolones): increased QT-interval prolongation

Drug-diagnostic tests. Alanine aminotransferase, aspartate aminotransferase, calcium, magnesium, white blood cells: increased levels

Glucose, potassium: altered levels

Hemoglobin, neutrophils, platelets: decreased values

Patient monitoring

See Watch for signs and symptoms of APL differentiation syndrome (fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions).

• Evaluate vital signs and neurologic status.

See Obtain baseline ECG; monitor ECG at least weekly.

• Assess for arrhythmias and conduction disorders.

See Discontinue drug and notify prescriber if patient develops syncope, tachycardia, or arrhythmias.

• Monitor serum electrolyte levels, CBC, and coagulation studies.

• Assess for hypoglycemia and hyperglycemia if patient is diabetic.

Patient teaching

See Watch for signs and symptoms of APL differentiation syndrome.

• Tell patient that drug increases risk of serious infection. Instruct him to report signs or symptoms of infection.

See Emphasize importance of avoiding pregnancy during therapy.

• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.

• Tell patient to minimize GI upset by eating small, frequent servings of food and drinking plenty of fluids.

• Advise patient to establish effective bedtime routine to minimize insomnia.

• Notify patient that he'll undergo regular blood testing during therapy.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

arsenic trioxide

(ar-sen-ik trye-ox-ide ) arsenictrioxide,

Trisenox

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: heavy metals
Pregnancy Category: D

Indications

genetic implication Induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who do not respond to or tolerate retinoid and anthracycline chemotherapy and whose disease is associated with the presence of the t(15; 17) translocation or PML/RAR-alpha gene expression.

Action

Alters DNA and fusion proteins in leukemic cells.

Therapeutic effects

Improved hematologic parameters in patients with APL.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.Distribution: Arsenic is stored in liver, kidney, heart, lung, hair and nails.Metabolism and Excretion: Converted from pentavalent arsenic to trivalent arsenic by arsenate reductase and further converted by methyltransferases in the liver. Methylated arsenic is excreted in urine.Half-life: Unknown.

Time/action profile (effect on hematologic parameters)

ROUTEONSETPEAKDURATION
IVunknownunknownunknown

Contraindications/Precautions

Contraindicated in: Hypersensitivity to arsenic; Obstetric: Can cause fetal injury; Lactation: Excreted in breast milk.Use Cautiously in: Severe renal impairment (dose ↓ may be needed if CCr <30 mL/min); Hepatic impairment; Concurrent use of other drugs that cause QT interval prolongation.Exercise Extreme Caution in: Pre-existing electrolyte abnormalities (correct prior to administration); concurrent use of drugs known to prolong QT interval, concurrent use of potassium wasting diuretics or amphotericin; Pediatric: Children <4 yr (safety not established).

Adverse Reactions/Side Effects

Central nervous system

  • fatigue
  • headache
  • insomnia
  • weakness

Respiratory

  • hypoxia (most frequent)
  • dyspnea
  • pleural effusion

Cardiovascular

  • torsade de pointes (life-threatening)
  • complete AV block (life-threatening)
  • atrial arrhythmias
  • QT interval prolongation

Gastrointestinal

  • abdominal pain (most frequent)
  • constipation
  • ↑ liver enzymes

Genitourinary

  • renal failure

Dermatologic

  • dermatitis

Endocrinologic

  • hyperglycemia
  • hypoglycemia

Fluid and Electrolyte

  • acidosis
  • hypocalcemia
  • hyperkalemia
  • hypokalemia
  • hypomagnesemia

Hematologic

  • neutropenia (life-threatening)
  • APL differentiation syndrome (life-threatening)
  • disseminated intravascular coagulation (life-threatening)
  • thrombocytopenia (life-threatening)
  • hyperleukocytosis
  • anemia
  • leukocytosis

Musculoskeletal

  • back pain (most frequent)
  • arthralgia
  • bone pain
  • neck pain
  • limb pain
  • myalgia

Miscellaneous

  • allergic reactions
  • fever
  • infection/sepsis

Interactions

Drug-Drug interaction

Use cautiously with other agents known to cause QT prolongation including some antiarrhythmics or thioridazine.Concurrent use of amphotericin B, potassium- or magnesium-wasting diuretics (↑ risk of serious arrhythmias).

Route/Dosage

Intravenous (Adults and Children ≥5 yr) Induction—0.15 mg/kg/day until bone marrow remission (not to exceed 60 doses); Consolidation—starting 3–6 wk after completion of induction; 0.15 mg/kg/day for 25 doses over a period of 5 wk.

Availability

Solution for injection : 1 mg/mL

Nursing implications

Nursing assessment

  • Assess for APL differentiation syndrome (fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis). Syndrome can be fatal. At first signs suggestive of syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest sounds or radiologic abnormalities) initiate high dose corticosteroids (dexamethasone 10 mg IV bid) irrespective of leukocyte count, and continue for at least 3 days or longer until symptoms have abated. Most patients do not require discontinuation of therapy.
  • Monitor ECG prior to initiation of therapy and weekly or more frequently for clinically unstable patients during induction or consolidation phase. May cause QT interval prolongation and may lead to a torsade de pointes-type arrhythmia, which may be fatal, and complete atrioventricular block. Risk of arrhythmia is increased with increased QT prolongation, concurrent administration of QT prolonging drugs, history of torsade de pointes, pre-existing QT interval prolongation, HF, administration of potassium-wasting diuretics, or other conditions resulting in hypokalemia or hypomagnesemia. Drugs known to cause prolonged QT interval should be discontinued if possible. For QTc >500 msec, corrective measures should be completed and QTc reassessed with serial ECGs prior to initiation of therapy. If QTc increases to >500 msec, reassess and take immediate corrective action and consider risk/benefit ratio of therapy. If syncope, rapid or irregular heartbeat develops, patient should be hospitalized for monitoring, serum electrolytes assessed, and therapy should be discontinued until the QTc interval is <460 msec, electrolyte abnormalities are corrected, and syncope and irregular heartbeat cease.
  • Monitor vital signs periodically throughout therapy. May cause hypotension or hypertension.
  • Lab Test Considerations: Monitor electrolyte, hematologic, and coagulation profiles at least twice weekly and more frequently for clinically unstable patients during induction phase and at least weekly during consolidation phase. May cause hypokalemia, hyperkalemia, hypomagnesemia, hyperglycemia, hypoglycemia, hypocalcemia, and acidosis. Potassium levels should be kept above 4 mEq/dL and magnesium concentrations should be kept above 1.8 mg/dL during therapy.
    • May cause ↑ ALT and AST concentrations.
    • May cause leukocytosis, anemia, thrombocytopenia, febrile neutropenia, neutropenia, and disseminated intravascular coagulation.
    • Symptoms of acute arsenic toxicity include convulsions, muscle weakness, and confusion. If these symptoms occur, discontinue therapy immediately and consider chelation therapy. Protocol for arsenic intoxication includes dimercaprol 3 mg/kg IM every 4 hr until immediate life-threatening toxicity has subsided. Then penicillamine 250 mg PO up to 4 times/day (<1 g/day) may be given.

Potential Nursing Diagnoses

Risk for injury (Side Effects)

Implementation

  • high alert: Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order, calculations and infusion pump settings. Arsenic trioxide should be administered under the supervision of a physician experienced in the management of patients with acute leukemia.
  • Intravenous Administration
  • Intermittent Infusion: Diluent: Dilute arsenic trioxide with 100-250 mL of D5W or 0.9% NaCl immediately after withdrawal from ampule. Discard unused portions. Diluted solution is stable at room temperature for 24 hr and for 48 hr when refrigerated.
  • Rate: Administer over 1–2 hr; may be extended up to 4 hr if acute vasomotor reactions are observed. Does not require a central venous catheter.
  • Y-Site Compatibility: alemtuzumab, amphotericin B lipid complex, anidulafungin, bivalirudin, daptomycin, ertapemen, octreotide, tigecycline, tirofiban

Patient/Family Teaching

  • Explain purpose of arsenic trioxide to patient.
  • Caution women of childbearing years to use effective contraception during therapy.

Evaluation/Desired Outcomes

  • Improved hematologic parameters in patients with APL.

Trisenox

A chemotherapeutic agent used for patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterised by the t(15;17) translocation or by PML/RAR-alpha gene expression.
Adverse effects
QT interval prolongation; complete atrioventricular block; APL differentiation (retinoic acid); syndrome-like symptoms (fever, dyspnoea, weight gain, pulmonary infiltrates, pleural or pericardial effusions, ± leukocytosis) which may be fatal.