ARSENIC TRIOXIDE 2 mg/mL Injection, Solution
🆔 Identity & classification
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This medicine belongs to the Other antineoplastic agents class.
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🩺 Clinical
Arsenic trioxide is used in combination with tretinoin to treat acute promyelocytic leukemia (APL; a type of cancer in which there are too many immature blood cells in the blood and bone marrow) in certain people as a first treatment. It is also used to treat APL in certain people who have not been helped by other types of chemotherapy or whose condition has improved but then worsened following treatment with a retinoid and other types of chemotherapy treatment(s). Arsenic trioxide is in a class of medications called anti-neoplastics. It works by slowing or stopping the growth of cancer cells.
Read the full MedlinePlus article ↗- Arsenic trioxide is used to treat a specific type of blood cancer called acute promyelocytic leukemia, or APL. This cancer involves abnormal white blood cells that carry a particul...
- What exactly is arsenic trioxide treating in my body?
- Arsenic trioxide is given as an intravenous infusion — directly into a vein — by a nurse or doctor, typically over about 2 hours. You'll receive it in a clinic or hospital setting,...
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UNII QTT17582CB
A strong acid used to adjust and maintain the proper pH level in liquid medicines, ensuring stability and preventing breakdown of active ingredients.
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UNII 55X04QC32I
A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
3 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Arsenic Trioxide 2 mg/mL 00781-3498-94 | Sandoz | 1 vial | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mL 23155-0870-41 | Heritage | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mL 25021-0227-06 | Sagent | 10 vials | — | AP | FDA listed | — |
| Arsenic trioxide 2 mg/mL 49315-0007-10 | Zydus | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mL 55150-0366-10 | Eugia | 1 vial | — | — | FDA listed | — |
| Trisenox 2 mg/mL 63459-0601-06 | Cephalon, | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mL 68083-0462-10 | Gland | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mL 70121-1658-01 | Amneal | 10 vials | — | AP | FDA listed | — |
| Arsenic trioxide 2 mg/mL 70710-1610-06 | Zydus | 10 vials | — | AP | FDA listed | — |
| Arsenic trioxide 2 mg/mL 70710-1896-06 | Zydus | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/2mL 72205-0172-07 | Novadoz | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mL 81607-0006-07 | Orbicular | 10 vials | — | AP | FDA listed | — |
| Arsenic Trioxide 2 mg/mLthis 83090-0010-01 | Sintetica | 1 vial | — | AP | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 83090-0010-01 You're viewing this | 1 VIAL, SINGLE-DOSE in 1 CARTON (83090-010-01) / 6 mL in 1 VIAL, SINGLE-DOSE (83090-010-05) | 2023-11-09 | Active |
| 83090-0010-10 | 10 VIAL, SINGLE-DOSE in 1 CARTON (83090-010-10) / 6 mL in 1 VIAL, SINGLE-DOSE (83090-010-05) | 2023-11-09 | Active |
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| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKES 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 [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, 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 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 arsenic trioxide 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. Temporarily withhold arsenic trioxide. ( 2.3 , 5.1 ) Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal.
Before administering arsenic trioxide, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide to patients with ventricular arrhythmia or prolonged QTc interval. Withhold arsenic trioxide until resolution and resume at reduced dose for QTc prolongation.
( 2.3 , 5.2 ) Serious encephalopathy, including Wernicke's, has occurred with 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.
( 5.3 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Arsenic trioxide injection is an arsenical 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. ( 1.2 )
1.2Relapsed or Refractory APL Arsenic trioxide injection is 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.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Relapsed or refractory APL: Induction: Administer 0.15 mg/kg/day intravenously daily until bone marrow remission. Do not exceed 60 days. ( 2.2 ) Consolidation: Administer 0.15 mg/kg/day intravenously daily for 25 doses over a period up to 5 weeks. ( 2.2 )
2.2Recommended Dosage for Relapsed or Refractory APL A treatment course for patients with relapsed or refractory APL consists of 1 induction cycle and 1 consolidation cycle [see Clinical Studies ( 14.2 )] . For the induction cycle, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily until bone marrow remission or up to a maximum of 60 days. For the consolidation cycle, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks.
Begin consolidation 3 to 6 weeks after completion of induction cycle.
2.3Monitoring and Dosage Modifications for Adverse Reactions During induction, monitor coagulation studies, blood counts, and chemistries at least 2 to 3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly. Table 2 shows the dosage modifications for adverse reactions due to arsenic trioxide injection when used alone.
Table 2: Dosage Modifications for Adverse Reactionsof Arsenic Trioxide Injection 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 back to the recommended dosage after one week on the reduced dose in the absence of worsening of hepatotoxicity. Discontinue the withheld drug 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). Modera…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Injection: 10 mg/10 mL (1 mg/mL) arsenic trioxide clear solution in a single-dose vial. Injection: 12 mg/6 mL (2 mg/mL) arsenic trioxide clear solution in a single-dose vial. Injection: 10 mg/10 mL (1 mg/mL) and 12 mg/6 mL (2 mg/mL) arsenic trioxide in single-dose vials. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Arsenic trioxide injection is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold arsenic trioxide for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution. ( 2.3 , 5.4 ) Carcinogenesis : Arsenic trioxide is a human carcinogen.
Monitor patients for the development of second primary malignancies. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception.
( 5.6 , 8.1 , 8.3 )
5.1Differentiation Syndrome Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide. In clinical trials, 16% to 23% of patients treated with arsenic trioxide for APL developed differentiation syndrome. Signs and symptoms include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction.
Differentiation syndrome has been observed with and without concomitant leukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. If differentiation syndrome is suspected, temporarily withhold arsenic trioxide and immediately initiate dexamethasone 10 mg intravenously every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for a minimum of 3 days [see Dosage and Administration ( 2.3 )] .
5.2Cardiac Conduction Abnormalities Patients treated with arsenic trioxide can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trial of patients with relapsed or refractory APL treated with arsenic trioxide monotherapy, 40% had at least one ECG tracing with a QTc interval greater than 500 msec. A prolonged QTc was observed between 1 and 5 weeks after start of arsenic trioxide infusion, and it usually resolved by 8 weeks after arsenic trioxide infusion.
There are no data on the effect of arsenic trioxide on the QTc interval during the infusion of the drug. The risk of torsade de pointes is related to the extent of QTc prolongation, concomitant administration of QTc prolonging drugs, a history of torsade de pointes, pre-existing QTc interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. The risk may be increased when arsenic trioxide is co-administered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) [see Drug Interactions ( 7 )] .
Prior to initiating therapy with arsenic trioxide, assess the QTc interval by electrocardiogram, correct pre-existing 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. If possible, discontinue drugs that are known to prolong the QTc interval.
If it is not possible to discontinue the interacting drug, perform cardiac monitoring frequently [see Drug Interactions ( 7 )] . During arsenic trioxide therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Monitor ECG weekly and more frequently for clinically unstable patients.
For patients who develop a QTc Framingham greater than 450 msec for men or greater than 460 msec for women, withhold arsenic trioxide and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume arsenic trioxide at a reduced dose [see Dosage and Administration ( 2.3 )] .
5.3Encephalopathy Serious encephalopathies were reported in patients receiving arsenic trioxide. Monitor patients for neurological symptoms,…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] Cardiac Conduction Abnormalities [see Warnings and Precautions ( 5.2 )] Encephalopathy [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Carcinogenesis [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (> 30%) are nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Orbicular Pharmaceutical Technologies Private Limited at 1-888-370-4186 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory APL Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of arsenic trioxide. Forty patients in the Study PLRXAS01 received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation cycles.
An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Serious adverse reactions observed in the 40 patients with refractory or relapsed APL enrolled in Study PLRXAS01 included differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2). The most common adverse reactions (> 30%) were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus.
Table 5 describes the adverse reactions in patients aged 5 to 73 years with APL who received arsenic trioxide at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received arsenic trioxide. Table 5: Adverse Reactions (≥ 5%) in Patients with Relapsed or Refractory APL Who Received Arsenic Trioxide in Study PLRXAS01 Body System Adverse reaction Any Grade Adverse Reactions Grade ≥3 Adverse Reactions n % n % Gastrointestinal disorders Nausea 30 75 Abdominal pain (lower & upper) 23 58 4 10 Vomiting 23 58 Diarrhea 21 53 Sore throat 14 35 Constipation 11 28 1 3 Anorexia 9 23 Appetite decreased 6 15 Loose stools 4 10 Dyspepsia 4 10 Oral blistering 3 8 Fecal incontinence 3 8 Gastrointestinal hemorrhage 3 8 Dry mouth 3 8 Abdominal tenderness 3 8 Diarrhea hemorrhagic 3 8 Abdominal distension 3 8 Respiratory Cough 26 65 Dyspnea 21 53 4 10 Epistaxis 10 25 Hypoxia 9 23 4 10 Pleural effusion 8 20 1 3 Post nasal drip 5 13 Wheezing 5 13 Decreased breath sounds 4 10 Crepitations 4 10 Rales 4 10 Hemoptysis 3 8 Tachypnea 3 8 Rhonchi 3 8 General disorders and administration site conditions Fatigue 25 63 2 5 Pyrexia (fever) 25 63 2 5 Edema - non-specific 16 40 Rigors 15 38 Chest pain 10 25 2 5 Injection site pain 8 20 Pain - non-specific 6 15 1 3 Injection site erythema 5 13 Weight gain 5 13 Injection site edema 4 10 Weakness 4 10 2 5 Hemorrhage 3 8 Weight loss 3 8 Drug hypersensitivity 2 5 1 3 Nervous system disorders Headache 24 60 1 3 Insomnia 17 43 1 3 Paresthesia 13 33 2 5 Dizziness (excluding vertigo) 9 23 Tremor 5 13 Convulsion 3 8 2 5 Somnolence 3 8 Coma 2 5 2 5 Cardiac disorders Tachycardia 22 55 ECG QT corrected interval prolonged > 500 msec 16 40 Palpitations 4 10 ECG abnormal other than QT interval pr…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS 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.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 2 ) Renal Impairment : Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with arsenic trioxide; dose reduction may be warranted. ( 8.6 ) Hepatic Impairment : Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with arsenic trioxide. ( 8.7 )
8.1Pregnancy 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/m 2 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/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 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/m 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/m 2 basis), on gestation days 6, 7, 8, or 9.
Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m 2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.
8.2Lactation Risk Summary Arsenic trioxide is excreted in human milk. There are no data on the effects of arsenic trioxide on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with arsenic trioxide and for 2 weeks after the final dose.
8.3Females and Males of Reproductive Potential Arsenic trioxide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Conduct pregnancy testing in females of reproductive potential prior to initiation of arsenic trioxide. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 6 month…
🤰 Pregnancy ▾
8.1Pregnancy 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/m 2 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/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 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/m 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/m 2 basis), on gestation days 6, 7, 8, or 9.
Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m 2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and efficacy of arsenic trioxide as a single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: 5 to 16 years) were treated with arsenic trioxide at the recommended dose of 0.15 mg/kg/day. A literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from 4 to 21 years.
No differences in efficacy and safety were observed by age.
🧓 Geriatric Use ▾
8.5Geriatric Use Use of arsenic trioxide as monotherapy in patients with relapsed or refractory APL is supported by the open-label, single-arm trial that included 6 patients aged 65 and older (range: 65 to 73 years). A literature review included an additional 4 patients aged 69 to 72 years who were treated with arsenic trioxide for relapsed or refractory APL. No overall differences in safety or effectiveness were observed between these patients and younger patients.
🆘 Overdosage ▾
10 OVERDOSAGE Manifestations Manifestations of arsenic trioxide overdosage include convulsions, muscle weakness, and confusion. Management For symptoms of arsenic trioxide overdosage, immediately discontinue arsenic trioxide and consider chelation therapy. A conventional protocol for acute arsenic intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided.
Thereafter, penicillamine at a dose of 250 mg orally, up to a maximum frequency of four times per day (≤ 1 g per day), may be given.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action The mechanism of action of arsenic trioxide is not completely understood. 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 promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-alpha.
12.2Pharmacodynamics Cardiac Electrophysiology In a single-arm trial of arsenic trioxide (0.15 mg/kg daily), 16 of 40 patients (40%) had a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after arsenic trioxide infusion, and then returned towards baseline by the end of 8 weeks after arsenic trioxide infusion.
12.3Pharmacokinetics The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As III ). As III is the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMA V ), and dimethylarsinic acid (DMA V ) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (As V ) a product of As III oxidation.
The pharmacokinetics of arsenical species ([As III ], [As V ], [MMA V ], [DMA V ]) were determined in 6 APL patients following once-daily doses of 0.15 mg/kg for 5 days per week. Over the total single-dose range of 7 mg to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. Peak plasma concentrations of arsenious acid (As III ), the primary active arsenical species were reached at the end of infusion (2 hours).
Plasma concentration of As III declined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to As III (mean AUC 0-24h ) was 194 ng∙hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng∙hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2-fold accumulation. The primary pentavalent metabolites, MMA V and DMA V , are slow to appear in plasma (approximately 10 to 24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does As III .
The mean estimated terminal elimination half-lives of the metabolites MMA V and DMA V are 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single-dose administration. As V is present in plasma only at relatively low levels.
Distribution The volume of distribution (V ss ) for As III is large (mean 562 L, N=10) indicating that As III is widely distributed throughout body tissues. V ss is also dependent on body weight and increases as body weight increases. Elimination Metabolism Much of the As III is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMA V ) and dimethylarsinic acid (DMA V ) by methyltransferases primarily in the liver.
The metabolism of arsenic trioxide also involves oxidation of As III to As V , which may occur in numerous tissues via enzymatic or nonenzymatic processes. As V is present in plasma only at relatively low levels following administration of arsenic trioxide. Excretion Approximately 15% of the administered arsenic trioxide dose is excreted in the urine as unchanged As III .
The methylated metabolites of As III (MMA V , DMA V ) are primarily excreted in the urine. The total clearance of As III is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on body weight or dose administered over the range of 7 mg to 32 mg.
Specific Populations Patients with Renal Impairment The effect of renal impairment on the pharmacokinetics of As III , As V , and the pentavalent metabolites MMA V and DMA V was evaluated in 20 patients with advanced malignancies. Patients were classified as having nor…
🧬 Mechanism of Action ▾
12.1Mechanism of Action The mechanism of action of arsenic trioxide is not completely understood. 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 promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-alpha.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Arsenic trioxide injection is supplied as a sterile, clear, colorless solution in glass, single-dose vials. It is available as follows: 10 mg/10 mL (1 mg/mL) Unit of Sale Each NDC number 83090-009-01 One Single-dose vial in a carton NDC number 83090-009-05 10 mL Single-dose vial (10 mL fill) NDC number 83090-009-10 10 Single-dose vials in a carton 12 mg/6 mL (2 mg/mL) Unit of Sale Each NDC number 83090-010-01 One Single-dose vial in a carton NDC number 83090-010-05 10 mL Single-dose vial (6 mL fill) NDC number 83090-010-10 10 Single-dose vials in a carton Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Do not freeze. Arsenic trioxide injection is a hazardous drug. Follow applicable special handling and disposal procedures.
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📋 Description ▾
11 DESCRIPTION Arsenic trioxide injection is a sterile injectable solution of arsenic trioxide. The molecular formula of arsenic trioxide in the solid state is As 2 O 3 , with a molecular weight of 197.84 g/mol and the following structural formula: Arsenic trioxide is a white to off-white powder. It is practically insoluble to sparingly soluble in water.
It dissolves in solutions of alkali hydroxides (NaOH 1 M). It is practically insoluble in ethanol, chloroform and ethyl ether. Arsenic trioxide injection is available in 10 mL single-dose vials containing 10 mg or 12 mg of arsenic trioxide.
Arsenic trioxide injection is formulated as a sterile, nonpyrogenic, clear solution of arsenic trioxide in water for injection using sodium hydroxide and dilute hydrochloric acid to adjust to pH 8. Arsenic trioxide injection is preservative-free. Arsenic trioxide, the active ingredient, is present at a concentration of 1 mg/mL and 2 mg/mL.
Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) for solubilization, and sodium hydroxide and hydrochloric acid for pH adjustment to pH 8. Image
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Differentiation Syndrome Advise patients that symptoms of APL differentiation syndrome include fever, sudden weight gain, dizziness/lightheadedness, labored breathing, and accumulation of fluid in the lungs, heart, and chest. This syndrome is managed by immediate treatment with high-dose corticosteroids. Advise patients to immediately report any of these symptoms [see Warnings and Precautions ( 5.1 )] .
Cardiac Conduction Abnormalities Advise patients that arsenic trioxide may cause ECG abnormalities, including QT prolongation. If extreme, this prolongation has the potential to cause fainting, irregular heartbeat, or more serious side effects. Advise patients to immediately report any of these symptoms.
Advise patients to provide a complete list of current medications as caution should be taken when arsenic trioxide is co-administered with other medications that can cause QT prolongation or lead to electrolyte abnormalities [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 )] . Encephalopathy and Wernicke's Encephalopathy (WE) Advise patients that symptoms of encephalopathies include neurological symptoms such as confusion, decreased level of consciousness, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction.
Advise patients and caregivers to closely monitor for neurological symptoms and immediately report them to their healthcare provider [see War nings and Precautions ( 5.3 )] . Advise patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide) that Wernicke's encephalopathy is a neurologic emergency that can be prevented and treated with thiamine supplementation, and to immediately report any neurological symptoms to their healthcare provider [see Warnings and Precautions ( 5.3 )] .
Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.5 ) and Use in Specific Populations 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 6 months after the last dose [see Use in Specific Populations ( 8.3 )] .
Advise males with female partners of reproductive potential to use effective contraception during treatment with arsenic trioxide for 3 months after the last dose [see Use in Specific Populations ( 8.3 )]. Lactation Advise women not to breastfeed during treatment with arsenic trioxide and for 2 weeks after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility Advise males of reproductive potential that arsenic trioxide may impair fertility [see Use in Specific Population ( 8.3 )] .
Other Adverse Reactions Advise patients of the expected adverse reactions of arsenic trioxide. Most patients in clinical trials experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal symptoms (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. Advise patients to call their healthcare provider at the onset of any adverse reactions [see Adverse Reactions ( 6.1 )] .