arsenic trioxide (Rx)

Brand and Other Names:Trisenox
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • 1mg/mL (10mg ampule)

Acute Promyelocytic Leukemia

Newly diagnosed low-risk acute promyelocytic leukemia (APL)

  • Indicated in combination with tretinoin for treatment of adults with newly diagnosed low risk APL whose APL has the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
  • 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

  • Indicated for induction of remission and consolidation in patients with 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
  • 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 

Dosage Modifications

Differentiation syndrome

  • Defined by the presence of ≥2 of the following: Unexplained fever, dyspnea; pleural and/or pericardial effusion; pulmonary infiltrates; renal failure; hypotension; weight gain >5 kg
  • Temporarily withhold arsenic trioxide
  • Consider holding tretinoin if symptoms are severe
  • Treat with dexamethasone 10 mg IV q12h until resolution of signs and symptoms for a minimum of 3 days
  • Resume treatment when the clinical condition improves and reduce dose of the withheld drug(s) by 50%
  • After 7 days on the reduced dose in the absence of differentiation syndrome, increase dose of withheld drug(s) to recommended dosage
  • If symptoms reappear, decrease arsenic trioxide and/or tretinoin to previous dose

QTc Prolongation

  • QTc prolongation >450 msec (men) or >460 msec (women)
  • Withhold treatment and any medication known to cause QT prolongation
  • Replete electrolytes
  • After QTc normalizes, resume arsenic trioxide at a 50% reduced dose (0.075 mg/kg qDay) for 7 days
  • If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase dose to 0.11 mg/kg qDay for 7 days
  • Dose can be increased to 0.15 mg/kg in the absence of QTc prolongation during that 14-day dose escalation period

Hepatoxicity

  • Defined by ≥1 of the following: Total bilirubin (TB) >3x ULN; AST >5x ULN; alkaline phosphatase (AP) >5x ULN
  • Withhold treatment with arsenic trioxide and/or tretinoin
  • Resume treatment at a 50% reduced dose of the withheld drug(s) when TB is <1.5x ULN and AP/AST are <3x ULN
  • After 7 days on the reduced dose in the absence of worsening of hepatotoxicity; increase dose of withheld drug(s) back to recommended dosage
  • Permanently discontinue the withheld drug(s) if hepatotoxicity recurs

Other severe or life-threatening (grade 3-4) nonhematologic reactions

  • Temporarily withhold arsenic trioxide and tretinoin
  • When adverse reaction resolves to ≤grade 1, resume treatment reduced by 2 dose levels (see below)

Moderate (grade 2) nonhematologic reactions

  • Reduce the dose of arsenic trioxide and/or tretinoin by 1 dose level (see below)

Leukocytosis (WBC count >10 Gi/L)

  • Administer hydroxyurea
  • Discontinue hydroxyurea when WBC <10 Gi/L

Myelosuppression

  • Defined by ≥1 following: ANC<1 Gi/L; platelets <50 Gi/L lasting more than 5 weeks
  • Consider reducing dose of arsenic trioxide and tretinoin by following: 1 dose level (see below)
  • If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess a marrow aspirate for remission weeks status
  • In the case of molecular remission, resume treatment at 1 dose level lower

Dosing reduction levels for hematologic and nonhematologic toxicities

  • Arsenic trioxide
    • Starting level: 0.15 mg/kg IV qDay
    • Level -1: 0.11 mg/kg IV qDay
    • Level -2: 0.1 mg/kg IV qDay
    • Level -3: 0.075 mg/kg IV qDay
  • Tretinoin
    • Starting level: 22.5 mg/m² PO BID
    • Level -1: 18.75 mg/m² PO BID
    • Level -2: 12.5 mg/m² PO BID
    • Level -3: 10 mg/m² PO BID

Renal impairment

  • Severe: (CrCl<30 mL/min): Exposure of arsenic trioxide may be higher; monitor for toxicities and dose reduce when warranted
  • Dialysis: Safety and efficacy not established

Hepatic impairment

  • Limited data available for all hepatic impairment groups; use with caution
  • Severe (Child Pugh C): Monitor for toxicities

Orphan Designations

Myelocytic leukemia subtypes MO, M1, M2, M4, M5, M6, and M7

Chronic lymphocytic leukemia

Malignant glioma

Myelodysplastic syndrome

Multiple myeloma

Liver cancer

Chronic myeloid leukemia

Amyotrophic lateral sclerosis

Acute promyelocytic leukemia (oral capsule)

Graft-versus-host disease

Orphan sponsors

  • Cephalon Inc; 41 Moores Road, P. O. Box 4011; Frazer, PA 19355
  • Terra Biological LLC; 3830 Valley Centre Drive, Suite 705-561; San Diego, California 92130
  • Orsenix Holdings BV; 1105 North Market Street, Suite 1800; Wilmington, Delaware 19801
  • Medsenicl 204 avenue de Colmar; Strasbourg, France

Dosage Forms & Strengths

injectable solution

  • 1mg/mL (10mg ampule)

Acute Promyelocytic Leukemia

Refractory or relapse after retinoid and anthracycline chemotherapy

  • Indicated 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
  • <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)

Dosing Considerations

Monitor: ECG, serum electrolytes

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Interactions

Interaction Checker

and arsenic trioxide

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            Adverse Effects

            >10%

            Nausea (75%)

            Cough (65%)

            Fatigue (63%)

            Pyrexia (63%)

            Headache (60%)

            Abdominal pain (58%)

            Vomiting (58%)

            Tachycardia (55%)

            Diarrhea (53%)

            Dyspnea (53%)

            Leukocytosis (50%)

            Pain (including bone pain, back pain, myalgia 50%)

            Hypokalemia (50%)

            Hypomagnesemia (45%)

            Hyperglycemia (45%)

            Insomnia (43%)

            Edema (40%)

            Sore throat (40%)

            Prolonged QTc interval (38%)

            Pruritus (33%)

            Dermatitis (33%)

            Parathesia (33%)

            Arthralgia (33%)

            Anxiety (30%)

            Constipation (28%)

            Chest pain (25%)

            Epistaxis (25%)

            Hypotension (25%)

            Anorexia/decreased appetite (23%)

            Dizziness (23%)

            Hypoxia (23%)

            ALT increased (20%)

            Depression (20%)

            Pleural effusion (20%)

            Sinusitis (20%)

            Thrombocytopenia (19%)

            Hyperkalemia (18%)

            Injection site reactions (4-15%)

            Anemia (14%)

            Febrile neutropenia (13%)

            Herpes simplex (13%)

            Tremor (13%)

            Upper respiratory infection (13%)

            Vaginal hemorrhage (13%)

            Weight gain (13%)

            1-10%

            Blurred vision (10%)

            Crepitation (10%)

            Eye irritation (10%)

            Flushing (10%)

            Hypertension (10%)

            Hypocalcemia (10%)

            Neutropenia (10%)

            Pallor (10%)

            Palpitations (10%)

            Rales (10%)

            Renal failure/impairment (8%)

            Anxiety (30%)

            Coma (5%)

            Confusion (5%)

            Tinnitus (5%)

            Convulsion (5%)

            Petechiae (8%)

            Eyelid edema (5%)

            Facial edema (8%)

            GI hemorrhage (8%)

            Hypoglycemia (8%)

            Hyperpigmentation (8%)

            Night sweats (8%)

            Oral candidiasis (5%)

            Urticaria (8%)

            Earache (8%)

            Postmarketing Reports

            Cardiac disorders: Ventricular extrasystoles in association with QT prolongation, ventricular tachycardia in association with QT prolongation, including torsade de pointes, atrioventricular block, and congestive heart failure

            Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion

            Hematologic disorders: Pancytopenia, bone marrow necrosis

            Infections and infestations: Herpes zoster

            Musculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysis

            Respiratory, thoracic, and mediastinal disorders: Differentiation syndrome

            Ear and labyrinth disorders: Deafness

            Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma

            Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis

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            Warnings

            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

            Contraindications

            Hypersensitivity

            Cautions

            Use caution in hepatic or renal impairment

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

            Differentiation syndrome, which may be life-threatening or fatal, observed in patients with acute promyelocytic leukemia (APL) treated with the drug (16-23% of patients developed differentiation syndrome; see Black Box Warnings and Dosage Modifications); the syndrome has been observed with and without concomitant hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as second month induction therapy; when therapy is used in combination with tretinoin, prednisone prophylaxis is advised; at the first signs of differentiation syndrome, interrupt treatment and administer dexamethasone 10 mg intravenously twice daily; continue high-dose steroids until signs and symptoms have abated for at least 3 days

            Prolongs QTc interval (see Black Box Warnings and Dosage Modifications); for patients who develop a QTc >500 msec, immediately withhold treatment and any medication known to prolong the QTc interval; correct electrolyte abnormalities; when QTc normalizes, resume therapy at a reduced dose

            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 (see Dosage Modifications)

            Fetal harm may occur when administered to a pregnant woman (see Pregnancy)

            Drug interactions overview

            • Coadministration with drugs that can prolong QT/QTc interval may increase the risk of serious QT/QTc interval prolongation
            • Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation
            • Coadministration with drugs that can lead to hepatotoxicity, particularly when given in combination with tretinoin, may increase the risk of serious hepatotoxicity
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            Pregnancy & Lactation

            Pregnancy

            No studies with arsenic trioxide in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform a drug associated risk of major birth defects and miscarriage

            Based on the mechanism of action and findings in animal studies, arsenic trioxide can cause fetal harm when administered to a pregnant woman

            Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose ~10 times the recommended human daily dose on a mg/m² basis

            A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose ~5 times the projected human dose on a mg/m² basis and in hamsters at an IV dose approximately equivalent to the projected human daily dose on a mg/m² basis

            Females and males of reproductive potential

            • Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment
            • Advise females of reproductive potential to use effective contraception during and after treatment and for 6 months after the final dose
            • Based on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, arsenic trioxide may impair fertility in males of reproductive potential

            Lactation

            Arsenic is excreted in milk

            Because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Causes apoptosis of promyelocytic leukemia cells; damages fusion protein PML-RAR alpha

            Absorption

            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)

            Distribution

            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

            AsV is present in plasma only at relatively low levels following administration of arsenic trioxide

            Elimination

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

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

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            Administration

            IV Compatibilities

            D5W

            0.9% NaCl

            IV Incompatibilities

            Do not mix with other medications

            IV Preparation

            Dilute in 100-250 mL D5W or 0.9% NaCl immediately after withdrawal from vial

            Do not save any unused portions for later administration

            IV Administration

            Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit

            Infuse over 2 hr; infusion duration may be extended up to 4 hr if acute vasomotor reactions are observed

            Central venous catheter is not required

            Vials are single-dose and do not contain preservatives

            Arsenic trioxide is a cytotoxic drug; follow special handling and disposal procedures

            Storage

            Unused vials: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59- 86°F)

            Diluted solutions: Store at room temperature [20-25°C (68-77°F)] for 24 hr and 48 hr when refrigerated

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            Formulary

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