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Arsenic Trioxide

Pronunciation

(AR se nik tri OKS id)

Index Terms

  • Arsenic (III) Oxide
  • As2O3
  • ATO

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Trisenox: 10 mg/10 mL (10 mL [DSC])

Solution, Intravenous [preservative free]:

Trisenox: 12 mg/6 mL (6 mL)

Brand Names: U.S.

  • Trisenox

Pharmacologic Category

  • Antineoplastic Agent, Miscellaneous

Pharmacology

Arsenic trioxide induces apoptosis in APL cells via morphological changes and DNA fragmentation; also damages or degrades the fusion protein promyelocytic leukemia (PML)-retinoic acid receptor (RAR) alpha

Distribution

Vdss: Arsenious acid (AsIII): 562 L; widely distributed throughout body tissues; dependent on body weight and increases as body weight increases; orally administered arsenic trioxide distributes into the CNS

Metabolism

Arsenic trioxide is immediately hydrolyzed to the active form, arsenious acid (AsIII) which is methylated (hepatically) to the less active pentavalent metabolites, monomethylarsonic acid (MMAv) and dimethylarsinic acid (DMAv) by methyltransferases; AsIII is also oxidized to the minor metabolite, arsenic acid (Asv)

Excretion

Urine (MMAv, DMAv, and ~15% of a dose as unchanged AsIII)

Time to Peak

AsIII: At the end of infusion (2 hours); MMAv and DMAv; ~10 to 24 hours

Half-Life Elimination

AsIII: 10 to 14 hours; MMAv: ~32 hours; DMAv: ~72 hours

Special Populations: Renal Function Impairment

Results from a pharmacokinetic study in patients with advanced malignancies showed that mean AUC for AsIII was ~48% higher in patients with several renal impairment (CrCl <30 mL/minute) than in patients with normal renal function (CrCl >80 mL/minute). Systemic exposure to metabolites MMAV and DMAV may also be increased in patients with renal impairment.

Special Populations: Hepatic Function Impairment

A small pharmacokinetic study in patients with hepatocellular carcinoma showed that the mean dose-normalized AUC and Cmax values were 40% and 70% higher, respectively, in a patient with severe hepatic impairment (Child-Pugh class C) versus patients with normal hepatic function. Additionally, the mean dose-normalized trough plasma levels for metabolites MMAV and DMAV were 2.2-fold and 4.7-fold higher, respectively, than levels in patients with normal hepatic function.

Use: Labeled Indications

Acute promyelocytic leukemia (newly diagnosed) (low-risk disease): Treatment of newly diagnosed low-risk acute promyelocytic leukemia (APL), in combination with tretinoin, in adults whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Acute promyelocytic leukemia (relapsed or refractory): Remission induction and consolidation treatment of APL in patients 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

Off Label Uses

Acute promyelocytic leukemia (newly diagnosed) (including intermediate- or high-risk disease) (adults)

Data from a randomized, multicenter, phase III study support the use of arsenic trioxide (in combination with tretinoin) in the management of intermediate-risk acute promyelocytic leukemia (APL) [Lo-Coco 2013], [Platzbecker 2017]. Data from a phase III study support the use of arsenic trioxide as a part of consolidation therapy in intermediate- and high-risk patients [Powell 2010]. Data from a phase III study support the use of arsenic (in combination with tretinoin and [for high-risk patients] gemtuzumab ozogamicin) for the treatment of newly diagnosed APL in all risk groups [Burnett 2015]. Data from a phase II study support the use of arsenic trioxide (in combination with tretinoin) for the treatment of APL in patients with intermediate-risk disease and (in combination with tretinoin and gemtuzumab ozogamicin) in patients with high-risk disease [Estey 2006], [Ravandi 2009]. Data from another phase II study support the use of arsenic trioxide (in combination with tretinoin and idarubicin) for the treatment of APL in all risk groups [Iland 2012]. These studies also included patients with newly diagnosed low-risk APL, which is a labeled indication.

Acute promyelocytic leukemia (newly diagnosed) (pediatrics)

Data from a phase II study support the use of arsenic trioxide (in combination with tretinoin) in the treatment of newly diagnosed APL in adolescent patients with low- to intermediate-risk disease [Ravandi 2009]. Data from another phase II study support the use of arsenic trioxide (in combination with tretinoin and idarubicin) for the treatment of newly diagnosed APL (in all risk groups) in pediatric patients [Iland 2012]. Data from another study supports the use of single-agent arsenic trioxide in the treatment of newly diagnosed APL in pediatric patients [Mathews 2006].

Contraindications

Hypersensitivity to arsenic or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Pregnancy; breast-feeding

Dosing: Adult

Note: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Acute promyelocytic leukemia (APL), newly diagnosed, low-risk: IV: Note: Prophylaxis for differentiation syndrome with prednisone 0.5 mg/kg/day is recommended starting on day 1 and continuing until the end of induction.

Induction (1 cycle): 0.15 mg/kg once daily (in combination with tretinoin); continue until bone marrow remission, not to exceed 60 days (Lo-Coco 2013; Platzbecker 2017)

Consolidation (4 cycles): 0.15 mg/kg once daily for 5 days each week during weeks 1 to 4 of each 8-week consolidation cycle (in combination with tretinoin) for a total of 4 consolidation cycles (Lo-Coco 2013; Platzbecker 2017)

APL (newly diagnosed, including intermediate- and/or high-risk disease) (off-label): IV:

APL0406 protocol: Intermediate-risk (Lo-Coco 2013; Platzbecker 2017):

Induction (1 cycle): 0.15 mg/kg once daily (in combination with tretinoin); continue until bone marrow remission, not to exceed 60 days

Consolidation (4 cycles): 0.15 mg/kg once daily for 5 days each week during weeks 1 to 4 of each 8-week consolidation cycle (in combination with tretinoin) for a total of 4 consolidation cycles

AML17 protocol (low-, intermediate-, or high-risk); in combination with tretinoin (Burnett 2015):

Induction (cycle 1): 0.3 mg/kg once daily on days 1 to 5 in week 1, followed by 0.25 mg/kg twice a week during weeks 2 to 8; high-risk patients were also administered a single dose of gemtuzumab within the first 4 days of treatment.

Consolidation (cycles 2 to 5): 0.3 mg/kg once daily on days 1 to 5 in week 1, followed by 0.25 mg/kg twice a week during weeks 2 to 4

C9710 protocol (low-, intermediate-, or high-risk); following remission induction with tretinoin, daunorubicin, and cytarabine, and followed by tretinoin (Powell 2010): Consolidation (2 courses): 0.15 mg/kg once daily on days 1 to 5 in each week during weeks 1 to 5; each course is separated by 2 weeks

Low-, intermediate-, or high-risk patients unable to tolerate anthracycline-based therapy; in combination with tretinoin (Estey 2006; Ravandi 2009):

Induction (1 cycle; beginning 10 days after initiation of tretinoin): 0.15 mg/kg once daily until bone marrow remission; maximum: 75 doses for induction; high-risk patients were also administered gemtuzumab on day 1 of induction

Consolidation (4 cycles): 0.15 mg/kg once daily on Monday through Friday for 4 weeks of every 8-week treatment cycle for 4 cycles (weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28)

APML4 protocol (low-, intermediate- and high-risk) (Iland 2012):

Induction (1 cycle): 0.15 mg/kg once daily on days 9 to 36 (in combination with tretinoin and age-adjusted idarubicin)

Consolidation (2 cycles): 0.15 mg/kg once daily on days 1 to 28 of consolidation cycle 1 (in combination with tretinoin); 0.15 mg/kg once daily on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33 of consolidation cycle 2 (in combination with tretinoin)

APL (relapsed or refractory): IV:

Induction (1 cycle): 0.15 mg/kg once daily until bone marrow remission; maximum: 60 doses for induction

Consolidation (1 cycle): 0.15 mg/kg once daily for 25 doses over a period of up to 5 weeks, beginning 3 to 6 weeks after completion of induction therapy

Dosing: Pediatric

Note: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Acute promyelocytic leukemia (APL), relapsed or refractory: Children ≥4 years of age: IV:

Induction (1 cycle): 0.15 mg/kg once daily until bone marrow remission; maximum: 60 doses for induction

Consolidation (1 cycle): 0.15 mg/kg once daily for 25 doses over a period of up to 5 weeks, beginning 3 to 6 weeks after completion of induction therapy

APL, newly diagnosed (off-label use): IV:

Induction, consolidation, and maintenance (Mathews 2006): Children ≥3 years of age and Adolescents:

Induction: 0.15 mg/kg once daily (maximum dose: 10 mg); administer daily until bone marrow remission; maximum: 60 doses for induction

Consolidation: 0.15 mg/kg once daily (maximum dose: 10 mg) for 4 weeks, starting 4 weeks after completion of induction therapy

Maintenance: 0.15 mg/kg once daily (maximum dose: 10 mg) administered 10 days per month for 6 months, starting 4 weeks after completion of consolidation therapy

APML4 protocol (Iland 2012): Low-, intermediate-, and high-risk: Children ≥3 years of age and Adolescents:

Induction: 0.15 mg/kg once daily on days 9 to 36 (in combination with tretinoin and idarubicin)

Consolidation (2 cycles): 0.15 mg/kg once daily on days 1 to 28 of consolidation cycle 1 (in combination with tretinoin); 0.15 mg/kg/day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33 of consolidation cycle 2 (in combination with tretinoin)

Low- risk; in combination with tretinoin (Ravandi 2009): Adolescents ≥14 years of age:

Induction (1 cycle; beginning 10 days after initiation of tretinoin): 0.15 mg/kg once daily until bone marrow remission; maximum: 75 doses for induction

Consolidation (4 cycles): 0.15 mg/kg once daily on Monday through Friday for 4 weeks of every 8-week treatment cycle for 4 cycles (weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28)

Dosing: Renal Impairment

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.

CrCl <30 mL/minute: Use with caution (systemic exposure to metabolites may be higher); may require dosage reduction; monitor closely for toxicity.

Dialysis patients: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Patients with severe impairment (Child-Pugh class C) should be monitored closely for toxicity.

Dosing: Adjustment for Toxicity

Dosage reduction levels (for hematologic and nonhematologic toxicities; tretinoin may also require dose reduction):

Initial dosage: 0.15 mg/kg once daily

First dose reduction level: 0.11 mg/kg once daily

Second dose reduction level: 0.1 mg/kg once daily

Third dose reduction level: 0.075 mg/kg once daily

Dosage adjustment when used alone or in combination with tretinoin:

Hematologic toxicities:

Leukocytosis (WBC >10,000/mm3): Administer hydroxyurea; may discontinue hydroxyurea when WBC declines to <10,000/mm3.

ANC <1,000/mm3: Consider reducing the dose (arsenic trioxide and tretinoin) by 1 dose level. If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide (and tretinoin) at 1 dose level lower.

Platelets <50,000/mm3: Consider reducing the dose (arsenic trioxide and tretinoin) by 1 dose level. If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide (and tretinoin) at 1 dose level lower.

Nonhematologic toxicities:

Differentiation syndrome (defined as the presence of 2 or more 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 withholding tretinoin if severe) and begin dexamethasone 10 mg IV every 12 hours until resolution of signs/symptoms for a minimum of 3 days. When clinical condition improves, resume treatment with the dose of the withheld drug(s) reduced by 50%. After 7 days, in the absence of recurrent symptoms, increase the dose to the recommended dosage. If symptoms recur, decrease arsenic and/or tretinoin to the previous dose.

Hepatotoxicity during treatment (defined as 1 or more of the following: total bilirubin >3 times the upper limit of normal (ULN), AST >5 times ULN, alkaline phosphatase >5 times ULN): Withhold arsenic trioxide and/or tretinoin. When total bilirubin <1.5 times ULN and AST/alkaline phosphatase <3 times ULN, resume treatment with the dose(s) reduced by 50%. After 7 days at the reduced dose(s), in the absence of worsening hepatotoxicity, increase the dose(s) back to the recommended dose(s). If hepatotoxicity recurs, discontinue permanently.

QTc prolongation >450 msec (for males) or >460 msec (for females): Withhold arsenic trioxide and any medication know to prolong the QTc interval. Replete electrolytes. After the QTc normalizes, resume arsenic trioxide with a 50% dose reduction (to 0.075 mg/kg once daily) for 7 days. If the 50% dose reduction is tolerated for 7 days, in the absence of QTc prolongation, increase the arsenic trioxide dose to 0.11 mg/kg once daily for 7 days. In the absence of QTc prolongation, the dose may be further increased to 0.15 mg/kg once daily during the 14-day dose escalation period.

Other nonhematologic reactions:

Moderate (grade 2): Reduce the dose (arsenic trioxide and/or tretinoin) by 1 dose level.

Severe or life-threatening (grade 3 or 4): Temporarily withhold arsenic trioxide and tretinoin. When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide and tretinoin with the dose reduced by 2 dose levels.

Reconstitution

Multiple concentrations: Arsenic trioxide is available as a 2 mg/mL solution (vial); previously, it was available as a 1 mg/mL solution (ampule). Verify concentration prior to admixture to assure appropriate dose preparation.

Dilute with 100 to 250 mL D5W or NS; dilute immediately after withdrawal from vial (discard unused portion of vial/ampule; do not save unused portion for later administration). Do not mix with other medications.

Administration

IV: Infuse over 2 hours. If acute vasomotor reactions occur, the infusion duration may be extended to up to 4 hours. Arsenic trioxide does not require administration via a central venous catheter.

Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Storage

Store intact vials/ampules at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Following dilution in D5W or NS, solutions diluted for infusion are stable for 24 hours at room temperature or 48 hours when refrigerated.

Drug Interactions

Amifampridine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bilastine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Buprenorphine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hydroxychloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Indapamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Macimorelin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Mizolastine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pefloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Probucol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Promazine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QTc-Prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of other QTc-Prolonging Agents (Highest Risk). Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Teneligliptin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination

Xipamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Tachycardia (55%), edema (40%), prolonged Q-T interval on ECG (40%; >500 msec), chest pain (25%), hypotension (25%)

Central nervous system: Fatigue (63%), headache (60%), insomnia (43%), rigors (38%), paresthesia (33%), anxiety (30%), dizziness (23%), depression (20%), pain (15%)

Dermatologic: Dermatitis (43%), pruritus (33%), xeroderma (15%), diaphoresis (13%), erythema (13%)

Endocrine & metabolic: Hypokalemia (50%), hyperglycemia (45%), hypomagnesemia (45%), hyperkalemia (18%), weight gain (13%)

Gastrointestinal: Nausea (75%), abdominal pain (58%), vomiting (58%), diarrhea (53%), sore throat (35%), constipation (28%), anorexia (23%), decreased appetite (15%)

Genitourinary: Vaginal hemorrhage (13%)

Hematologic & oncologic: Leukocytosis (50%; grades 3/4: 3%), APL differentiation syndrome (16% to 23%; grades 3/4: 8%), anemia (20%; grades 3/4: 5%), bruise (20%), thrombocytopenia (18%; grades 3/4: 13%), febrile neutropenia (13%; grades 3/4: 8%)

Hepatic: Increased serum ALT (20%), increased serum AST (13%)

Infection: Herpes simplex infection (13%)

Local: Pain at injection site (20%), erythema at injection site (13%)

Neuromuscular & skeletal: Arthralgia (33%), myalgia (25%), ostealgia (23%), back pain (18%), limb pain (13%), neck pain (13%), tremor (13%)

Respiratory: Cough (65%), dyspnea (53%), epistaxis (25%), hypoxia (23%), pleural effusion (20%), sinusitis (20%), post nasal drip (13%), upper respiratory tract infection (13%), wheezing (13%)

Miscellaneous: Fever (63%)

1% to 10%:

Cardiovascular: Hypertension (10%), flushing (10%), palpitations (10%), ECG abnormality (8%; non-QT prolongation), facial edema (8%), atrial arrhythmia (5%), torsades de pointes (3%)

Central nervous system: Drowsiness (8%), seizure (8%), agitation (5%), coma (5%), confusion (5%)

Dermatologic: Pallor (10%), hyperpigmentation (8%), night sweats (8%), skin lesion (8%), urticaria (8%)

Endocrine & metabolic: Hypocalcemia (10%), hypoglycemia (8%), intermenstrual bleeding (8%), weight loss (8%), acidosis (5%)

Gastrointestinal: Dyspepsia (10%), loose stools (10%), abdominal distension (8%), abdominal tenderness (8%), bloody diarrhea (8%), fecal incontinence (8%), gastrointestinal hemorrhage (8%), oral bullae (8%), xerostomia (8%), oral candidiasis (5%)

Genitourinary: Oliguria (5%), urinary incontinence (5%)

Hematologic & oncologic: Neutropenia (10%; grades 3/4: 10%), disseminated intravascular coagulation (8%; grades 3/4: 8%), hemorrhage (8%), hyperleukocytosis (grades 3/4: 8%), lymphadenopathy (8%), petechia (8%)

Hypersensitivity: Hypersensitivity reaction (5%)

Infection: Bacterial infection (8%), herpes zoster (8%), sepsis (5%)

Local: Swelling at injection site (10%), local skin exfoliation (5%)

Neuromuscular & skeletal: Weakness (10%)

Ophthalmic: Blurred vision (10%), eye irritation (10%), xerophthalmia (8%), eye redness (with pain: 5%), eyelid edema (5%)

Otic: Otalgia (8%), tinnitus (5%)

Renal: Renal failure (8%), renal insufficiency (8%)

Respiratory: Abnormal breath sounds (decreased: 10%), rales (10%), hemoptysis (8%), rhonchi (8%), tachypnea (8%), nasopharyngitis (5%)

<1%, postmarketing, and/or case reports: Atrioventricular block, bone marrow necrosis, cardiac failure, deafness, heart block, increased gamma-glutamyl transferase, malignant melanoma, pancytopenia, paresis, peripheral neuropathy, rhabdomyolysis, squamous cell carcinoma, toxic epidermal necrolysis, ventricular premature contractions, ventricular tachycardia

ALERT: U.S. Boxed Warning

Differentiation syndrome:

Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide have experienced symptoms of differentiation syndrome, 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 multiorgan dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Temporary discontinuation of arsenic trioxide may be required.

QT prolongation:

Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a torsade des pointes-type ventricular arrhythmia, which can be fatal. Before initiating therapy, assess the QTc interval, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide to patients with ventricular arrhythmia or prolonged QTcF.

Warnings/Precautions

Concerns related to adverse effects:

• Differentiation syndrome: [US Boxed Warning]: Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide have experienced symptoms of differentiation syndrome (may be fatal if not treated). Symptoms may include fever (unexplained), dyspnea, acute respiratory distress, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multiorgan dysfunction, occurring with or without leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until signs/symptoms resolve. May require temporary discontinuation of arsenic trioxide. The onset of differentiation syndrome has occurred as early as day 1 of induction to as late as the second month of induction therapy. Prophylaxis with prednisone is recommended when arsenic trioxide is used in combination with tretinoin. At the first signs of differentiation syndrome, interrupt arsenic trioxide and administer dexamethasone 10 mg IV twice daily; continue high-dose corticosteroids until signs/symptoms have abated for at least 3 days.

• Gastrointestinal toxicity: Arsenic trioxide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

• Hepatotoxicity: In newly diagnosed low-risk APL studies, patients treated with arsenic trioxide in combination with tretinoin experienced elevated AST, alkaline phosphatase, and/or serum bilirubin, which usually resolved with temporary discontinuation of arsenic trioxide and/or tretinoin. Monitor LFTs at least 2 to 3 times a week during arsenic trioxide treatment and continue monitoring until toxicity recovers. Withhold arsenic trioxide treatment and/or tretinoin if AST, alkaline phosphatase, and/or serum bilirubin elevations >5 times the ULN occur. Long-term hepatic abnormalities may occur in patients with APL treated with arsenic trioxide in combination with tretinoin. Mild hepatic dysfunction and hepatic steatosis have been observed at a median of 7 years (range: up to 14 years) following arsenic trioxide and tretinoin combination therapy.

• QT prolongation: [US Boxed Warning]: Arsenic trioxide may cause QTc interval prolongation, atrioventricular block, and a torsade des pointes-type ventricular arrhythmia, which may be fatal. Prior to treatment initiation, assess the QTc interval (by ECG), correct preexisting electrolyte abnormalities, and consider discontinuing medications known to prolong QTc interval. Do not administer arsenic trioxide to patients with ventricular arrhythmia or prolonged QTcF. In newly diagnosed low-risk APL studies, some patients who received arsenic trioxide in combination with tretinoin experienced QTc prolongation >450 msec (for males) and >460 msec (for females) throughout treatment cycles. In studies for relapsed or refractory APL, over one-third of patients who received arsenic trioxide (as monotherapy) had at least one ECG with a QTc interval >500 msec. Prolonged QTc has been observed between 1 and 5 weeks after start of arsenic trioxide treatment, and usually resolved by 8 weeks after treatment. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion. The risk of torsades de pointes is related to the extent of QTc prolongation, concurrent use of QTc prolonging medications, a history of torsade des pointes, preexisting QTc interval prolongation, heart failure, concurrent potassium-wasting diuretics, or other conditions associated with hypokalemia or hypomagnesemia. The risk may be increased when arsenic trioxide is coadministered with medications associated with electrolyte abnormalities (eg, diuretics or amphotericin B). If it is not possible to discontinue concomitant medications associated with QTc prolongation, perform cardiac monitoring frequently. Maintain serum potassium >4 mEq/L and magnesium >1.8 mg/dL during treatment. Monitor ECG weekly (more frequently in clinically unstable patients). If QTc >500 msec develops, immediately withhold arsenic trioxide treatment and any medication known to prolong the QTc interval and correct electrolyte abnormalities; when the QTc normalizes, resume arsenic trioxide at a reduced dose.

• Secondary malignancy: Arsenic trioxide is a human carcinogen; monitor for the development of second primary malignancies.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; monitor closely for toxicity in patients with severe hepatic impairment.

• Renal impairment: Use with caution in patients with severe renal impairment (dose reduction may be warranted); systemic exposure may be higher; monitor closely for toxicities. Arsenic trioxide has not been studied in dialysis patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Multiple concentrations: Arsenic trioxide is available in different concentrations; verify concentration prior to admixture to assure appropriate dose preparation.

Monitoring Parameters

Monitor electrolytes (potassium, calcium, and magnesium), CBC with differential, renal function (serum creatinine), hepatic function, blood glucose, and coagulation parameters at baseline then at least 2 to 3 times a week during induction and at least weekly during consolidation; more frequent monitoring may be necessary in unstable patients; pregnancy test (prior to treatment in females of reproductive potential); baseline then weekly 12-lead ECG; signs/symptoms of APL differentiation syndrome (unexplained fever, dyspnea, and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities).

Pregnancy Considerations

Based on the mechanism of action and findings in animal reproduction studies, arsenic may cause fetal harm if administered during pregnancy. Arsenic crosses the human placenta. In studies of women exposed to high levels of arsenic from drinking water, cord blood levels were similar to maternal serum levels. Dimethylarsinic acid (DMA) was the form of arsenic found in the fetus. An increased risk of low birth weight and still births were observed in women who ingested high levels of dietary arsenic. Verify pregnancy status in females of reproductive potential prior to initiating therapy. Females of reproductive potential should use effective contraception during treatment and for 6 months after the final arsenic trioxide dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the final arsenic trioxide dose. An international consensus panel has published guidelines for the management of hematologic malignancies during pregnancy; arsenic trioxide is teratogenic and should not be used throughout pregnancy (Lishner 2016). Arsenic trioxide may impair fertility in males of reproductive potential (based on findings in animal studies).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, abdominal pain, diarrhea, lack of appetite, weight gain, weight loss, dry mouth, insomnia, fatigue, bone pain, injection site pain or irritation, dry eyes, pale skin, anxiety, joint pain, muscle pain, back pain, sweating a lot, painful extremities, dry skin, flushing, neck pain, ear pain, skin irritation, or eye irritation. Have patient report immediately to prescriber abnormal heartbeat, signs of retinoic-acid-APL syndrome (fever, shortness of breath, difficulty breathing, or weight gain), signs of infection, signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), angina, tachycardia, edema, severe dizziness, passing out, severe headache, vision changes, severe loss of strength and energy, depression, seizures, burning or numbness feeling, blurred vision, tremors, shortness of breath, fast breathing, confusion, agitation, or tinnitus (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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