Arsenic trioxide
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, and ENCEPHALOPATHY INCLUDING WERNICKE'S Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide have experienced differentiation syndrome, which may be life-threatening or fatal. Signs and symptoms may include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain, peripheral edema, hypotension, renal insufficiency , hepatopathy, and multi-organ dysfunction, in the presence or absence of leukocytosis.
If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold arsenic trioxide injection [see Dosage and Administration ( 2.3 ), Warnings and Precautions (5.1) ]. Cardiac Conduction Abnormalities: Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering arsenic trioxide injection, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide to patients with a ventricular arrhythmia or prolonged QTc interval.
Withhold arsenic trioxide injection until resolution and resume at reduced dose for QTc prolongation [ see Dosage and Administration ( 2.3 ), Warnings and Precautions (5.2) ]. Encephalopathy: Serious encephalopathy, including Wernicke’s, has occurred with arsenic trioxide. Wernicke’s is a neurologic emergency. Consider testing thiamine levels in patients at risk for thiamine deficiency. Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving arsenic trioxide. If Wernicke’s encephalopathy is suspected, immediately interrupt arsenic trioxide and initiate parenteral thiamine.
Monitor until symptoms resolve or improve and thiamine levels normalize [ see Warnings and Precautions (5.3) ]. WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, and ENCEPHALOPATHY INCLUDING WERNICKE’S See full prescribing information for complete boxed warning. Patients with acute promyelocytic leukemia (APL) treated with a rsenic trioxide i nj e c t io n have experienced symptoms of differentiation syndrome, which may be life-threatening or fatal. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution.…
Dosing in kidney impairment
Renal Impairment Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology ] . Monitor patients with severe renal impairment (creatinine clearance [CL CR ] less than 30 mL/min) frequently for toxicity; a dose reduction may be warranted. The use of arsenic trioxide in patients on dialysis has not been studied.
| Adverse Reaction | Dosage Modification |
|---|---|
| Differentiation syndrome, defined by the presence of 2 or more of the following: − Unexplained fever − Dyspnea − Pleural and/or pericardial effusion − Pulmonary infiltrates − Renal failure − Hypotension − Weight gain greater than 5 kg [see Warnings and Precautions (5.1)] | Temporarily withhold arsenic trioxide injection.Administer dexamethasone 10 mg intravenously every 12 hours until the resolution of signs and symptoms for a minimum of 3 days.Resume treatment when the clinical condition improves and reduce the dose of the withheld drug(s) by 50%.Increase the dose of the withheld drug(s) to the recommended dosage after one week in the absence of recurrence of symptoms of differentiation syndrome.If symptoms re-appear, decrease arsenic trioxide injection to the previous dose. |
| QTc (Framingham formula) Prolongation greater than 450 msec for men or greater than 460 msec for women [see Warnings and Precautions (5.2)] | Withhold arsenic trioxide injection and any medication known to prolong the QTc interval.Correct electrolyte abnormalities.After the QTc normalizes and electrolyte abnormalities are corrected, resume treatment with arsenic trioxide injection at a 50% reduced dose (0.075 mg/kg/day daily) for one week after resolution.If the 50% reduced dose is tolerated for one week (in the absence of QTc prolongation), increase the dose of arsenic trioxide injection to 0.11 mg/kg/day daily for the next week.The dose of arsenic trioxide injection can be increased to 0.15 mg/kg/day in the absence of QTc prolongation during that 14-day dose-escalation period. |
| Hepatotoxicity, defined by 1 or more of the following: − Total bilirubin (TB) greater than 3 times the upper limit of normal (ULN) − Aspartate aminotransferase (AST) greater than 5 times the ULN − Alkaline phosphatase (AP) greater than 5 times the ULN [see Warnings and Precautions (5.4)] | Withhold arsenic trioxide injection.Resume treatment at a 50% reduced dose of the withheld drug(s) when TB is less than 1.5 times the ULN and AP/AST are less than 3 times the ULN.Increase the dose of the withheld drug(s) back to the recommended dosage after one week on the reduced dose in the absence of worsening of hepatotoxicity.Discontinue the withheld drug(s) permanently if hepatotoxicity recurs. |
| Other severe or life-threatening (grade 3 to 4) nonhematologic reactions [see Adverse Reactions (6)] | Temporarily withhold arsenic trioxide injection.When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide injection reduced by 2 dose levels (see Table 3 below). |
| Moderate (grade 2) nonhematologic reactions [see Adverse Reactions (6)] | Reduce the dose of arsenic trioxide injection by 1 dose level (see Table 3 below). |
| Leukocytosis (WBC count greater than 10 Gi/L) [see Adverse Reactions (6.1)] | Administer hydroxyurea.Hydroxyurea may be discontinued when the WBC declines below 10 Gi/L. |
| Myelosuppression, defined by 1 or more of the following: − absolute neutrophil count less than 1 Gi/L − platelets less than 50 Gi/L lasting more than 5 weeks [see Adverse Reactions (6)] | Consider reducing the dose of arsenic trioxide injection by 1 dose level (see Table 3 below).If myelosuppression lasts ≥50 days or occurs on 2 consecutive cycles, assess a marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide injection at 1 dose level lower (see Table 3 below). |
Dosing in liver impairment
Hepatic Impairment Since limited data are available across all hepatic impairment groups, caution is advised in the use of arsenic trioxide in patients with hepatic impairment [see Clinical Pharmacology ] . Monitor patients with severe hepatic impairment (Child-Pugh Class C) frequently for toxicity.
Preparation and administration
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Preparation and Administration Reconstitution Dilute arsenic trioxide injection with 100 to 250 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, using proper aseptic technique, immediately after withdrawal from the vial. Do not save any unused portions for later administration. After dilution, store arsenic trioxide injection for no more than 24 hours at room temperature and 48 hours when refrigerated.
Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administer arsenic trioxide injection as an intravenous infusion over 2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed.
A central venous catheter is not required. The arsenic trioxide injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly. Do not mix arsenic trioxide injection with other medications. Safe Handling Procedures Arsenic trioxide injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1
Drug interactions
Check arsenic trioxide against a medication listLabel text (2 paragraphs)
Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and arsenic trioxide may increase the risk of serious QT/QTc interval prolongation [see Warnings and Precautions (5.1) ] . Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while the patient is using arsenic trioxide. Monitor ECGs more frequently in patients when it is not feasible to avoid concomitant use. Drugs That Can Lead to Electrolyte Abnormalities Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation [see Warnings and Precautions (5.1) ] . Avoid concomitant use of drugs that can lead to electrolyte abnormalities.
Monitor electrolytes more frequently in patients who must receive concomitant use of these drugs and arsenic trioxide. Drugs That Can Lead to Hepatotoxicity Use of these drugs and arsenic trioxide may increase the risk of serious hepatotoxicity [see Warnings and Precautions (5.4) ] . Discontinue or replace with an alternative drug that does not cause hepatotoxicity while the patient is using arsenic trioxide. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.
Contraindications
Arsenic trioxide is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic. ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1) ] 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 approximately 10 times the recommended human daily dose on a mg/m² basis ( see Data ). A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis.
There are no studies with the use of 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. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Human Data One patient was reported to deliver a live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. A second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have a normal pregnancy outcome. A third patient was a pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had a normal pregnancy outcome after treatment and monitoring. A fourth patient who became pregnant while receiving arsenic trioxide had a miscarriage.
Animal Data Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were observed in rats administered 10 mg/kg of arsenic trioxide on gestation day 9 (approximately 10 times the recommended human daily dose on a mg/m² basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite (approximately 5 times the projected human dose on a mg/m² basis), on gestation days 6, 7, 8, or 9. Intravenous injection of 2…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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