NDC 49315-007 Arsenic Trioxide

Arsenic Trioxide

NDC Product Code 49315-007

NDC 49315-007-10

Package Description: 10 VIAL in 1 CARTON > 6 mL in 1 VIAL (49315-007-01)

NDC Product Information

Arsenic Trioxide with NDC 49315-007 is a a human prescription drug product labeled by Alidac Pharmaceuticals Limited. The generic name of Arsenic Trioxide is arsenic trioxide. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Alidac Pharmaceuticals Limited

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Arsenic Trioxide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ARSENIC TRIOXIDE 2 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

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  • Intravenous - Administration within or into a vein or veins.

Product Labeler Information

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Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Alidac Pharmaceuticals Limited
Labeler Code: 49315
FDA Application Number: ANDA206228 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-03-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
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* Please review the disclaimer below.

Arsenic Trioxide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Boxed Warning

WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKE'SDifferentiation 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 multi-organ 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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].Cardiac Conduction Abnormalities: Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a 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 arsenic trioxide to patients with ventricular arrhythmia or prolonged QTcF [see Warnings and Precautions (5.2)].Encephalopathy: Serious encephalopathy, including Wernicke's, has occurred in patients treated 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 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)].

1.2 Relapsed Or Refractory Apl

Arsenic trioxide injection is 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.

  • Relapsed or Refractory APLA treatment course including arsenic trioxide monotherapy 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 dose of arsenic trioxide is 0.15 mg/kg intravenously daily until bone marrow remission or up to a maximum of 60 days.For the consolidation cycle, the recommended dose of arsenic trioxide is 0.15 mg/kg intravenously daily for 25 doses over a period of up to 5 weeks.  Begin consolidation 3 to 6 weeks after completion of induction therapy.

2.2 Dose Modifications For Toxicities

  • During induction therapy, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery.  During consolidation, monitor at least weekly.  Management of some adverse reactions may require dose interruption, dose reduction, or permanent discontinuation of arsenic trioxide [see Warnings and Precautions (5) and Adverse Reactions (6)]. Table 2 shows the dose modifications for toxicity due to arsenic trioxide when used alone. Table 2:  Dose Adjustments for Adverse Reactions   Adverse Reaction(s)   Dose 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 Temporarily withhold arsenic trioxide.  Treat with 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 7 days in the absence of recurrence of symptoms of differentiation syndrome.If symptoms re-appear, decrease arsenic trioxide to the previous dose. QTc Prolongation greater than 450 msec for men or greater than 460 msec for women:Withhold treatment with arsenic trioxide and any medication known to prolong the QTc interval.Replete electrolytes.After the QTc normalizes, resume treatment with arsenic trioxide at a 50% reduced dose (0.075 mg/kg once daily) for 7 days.If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase the dose of arsenic trioxide to 0.11 mg/kg once daily for 7 days.The dose of arsenic trioxide can be increased to 0.15 mg/kg 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 Withhold treatment with arsenic trioxide. 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 7 days 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 3-4) nonhematologic reactionsTemporarily withhold arsenic trioxide.When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide reduced by 2 dose levels (see Table 3 below). Moderate (grade 2) nonhematologic reactionsReduce the dose of arsenic trioxide by 1 dose level (see Table 3 below). Leukocytosis (WBC count greater than 10 Gi/L)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 weeksConsider reducing the dose of arsenic trioxide 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 at 1 dose level lower (see Table 3 below). Table 3: Dose Reduction Levels for Hematologic and Nonhematologic Toxicities Dose Level Arsenic trioxide mg/kg intravenously once daily Starting level 0.15 -1 0.11 -2 0.10 -3 0.075

2.3 Instructions For Preparation And Intravenous Administration

ReconstitutionDilute arsenic trioxide 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, arsenic trioxide is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.AdministrationParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Administer arsenic trioxide intravenously 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 vial is single-dose and does not contain any preservatives. Unused portions of each vial should be discarded properly. Do not mix arsenic trioxide with other medications.Safe Handling ProceduresArsenic trioxide is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

3 Dosage Forms And Strengths

Injection: 12 mg arsenic trioxide in 6 mL in single-dose vial.

4 Contraindications

Arsenic trioxide is contraindicated in patients who are hypersensitive to arsenic.

5.1 Differentiation 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, 16-23% of patients treated with arsenic trioxide for APL developed differentiation syndrome.  Symptoms include unexplained fever, dyspnea, hypoxia, 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 hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy.At the first signs of differentiation syndrome, interrupt treatment with arsenic trioxide and administer dexamethasone 10 mg intravenously twice daily.  Continue high-dose steroids until signs and symptoms have abated for at least 3 days [see Dosage and Administration (2.2)].

5.2 Cardiac Conduction Abnormalities

Patients treated with arsenic trioxide can develop QTc prolongation, torsade de pointes, and complete heart 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 coadministered 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 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 greater than 500 msec, immediately withhold treatment with arsenic trioxide and any medication known to prolong the QTc interval.  Correct electrolyte abnormalities. When the QTc normalizes, resume arsenic trioxide at a reduced dose [see Dosage and Administration (2.2)].

5.3 Encephalopathy

Serious encephalopathies were reported in patients receiving arsenic trioxide. Monitor patients for neurological symptoms such as confusion, decreased level of consciousness, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction. Advise patients and caregivers of the need for close observation. Wernicke's EncephalopathyWernicke's encephalopathy occurred in patients receiving arsenic trioxide. Wernicke's encephalopathy is a neurologic emergency that can be prevented and treated with thiamine. Consider testing thiamine levels in patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide). 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.

5.4 Hepatotoxicity

During treatment with arsenic trioxide, monitor liver chemistries at least 2-3 times per week through recovery from toxicities. Withhold treatment with arsenic trioxide if elevations in aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin occur to greater than 5 times the upper limit of normal [see Dosage and Administration (2.2)].Long-term liver abnormalities can occur in APL patients treated with arsenic trioxide.

5.5 Carcinogenesis

The active ingredient arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

5.6 Embryo-Fetal Toxicity

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. 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. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with arsenic trioxide [see Use in Specific Populations (8.1, 8.3)].

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)]Embryo-Fetal Toxicity [see Warnings and Precautions (5.6)]

6.1 Clinical 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 APLSafety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of arsenic trioxide.  Forty patients in the Phase 2 study received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Most patients experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.SAEs, Grade ≥3 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to arsenic trioxide in the Phase 2 study of 40 patients with refractory or relapsed APL included APL 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).Table 5 describes the adverse reactions that were observed in ≥ 5% patients, between the ages of 5-73 years, treated for APL with 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 (Any Grade) Occurring in ≥ 5% of Patients Treated with Arsenic Trioxide Monotherapy for Relapsed or Refractory APL 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 prolongation 3 8 Metabolism and nutrition disorders Hypokalemia 20 50 5 13 Hypomagnesemia 18 45 5 13 Hyperglycemia 18 45 5 13 ALT increased 8 20 2 5 Hyperkalemia 7 18 2 5 AST increased 5 13 1 3 Hypocalcemia 4 10 Hypoglycemia 3 8 Acidosis 2 5 Hematologic disorders Leukocytosis 20 50 1 3 Anemia 8 20 2 5 Thrombocytopenia 7 18 5 13 Febrile neutropenia 5 13 3 8 Neutropenia 4 10 4 10 Disseminated intravascular coagulation 3 8 3 8 Lymphadenopathy 3 8 Skin and subcutaneous tissue disorders Dermatitis 17 43 Pruritus 13 33 1 3 Ecchymosis 8 20 Dry skin 6 15 Erythema - non-specific 5 13 Increased sweating 5 13 Facial edema 3 8 Night sweats 3 8 Petechiae 3 8 Hyperpigmentation 3 8 Non-specific skin lesions 3 8 Urticaria 3 8 Local exfoliation 2 5 Eyelid edema 2 5 Musculoskeletal, connective tissue, and bone disorders Arthralgia 13 33 3 8 Myalgia 10 25 2 5 Bone pain 9 23 4 10 Back pain 7 18 1 3 Neck pain 5 13 Pain in limb 5 13 2 5 Psychiatric disorders Anxiety 12 30 Depression 8 20 Agitation 2 5 Confusion 2 5 Vascular disorders Hypotension 10 25 2 5 Flushing 4 10 Hypertension 4 10 Pallor 4 10 Infections and infestations Sinusitis 8 20 Herpes simplex 5 13 Upper respiratory tract infection 5 13 1 3 Bacterial infection - non-specific 3 8 1 3 Herpes zoster 3 8 Nasopharyngitis 2 5 Oral candidiasis 2 5 Sepsis 2 5 2 5 Reproductive system disorders Vaginal hemorrhage 5 13 Intermenstrual bleeding 3 8 Ocular disorders Eye irritation 4 10 Blurred vision 4 10 Dry eye 3 8 Painful red eye 2 5 Renal and urinary disorders Renal failure 3 8 1 3 Renal impairment 3 8 Oliguria 2 5 Incontinence 2 5 Ear disorders Earache 3 8 Tinnitus 2 5Leukocytosis: Leukocytosis greater than 10 Gi/L developed during induction therapy in 50% of patients receiving arsenic trioxide monotherapy for relapsed/refractory APL. In the relapsed/refractory setting, a relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts. Hyperleukocytosis due to arsenic trioxide may warrant treatment with hydroxyurea [see Dosage and Administration (2.2)].

6.2 Postmarketing Experience

The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are voluntarily reported from a population of unknown size, precise estimates of frequency or causal relationship to drug exposure cannot always be made.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 failureNervous system disorders: Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernicke's encephalopathy, posterior reversible encephalopathy syndromeHematologic disorders: Pancytopenia, bone marrow necrosisInfections and infestations: Herpes zosterInvestigations: Gamma-glutamyltransferase increasedMusculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysisRespiratory, thoracic, and mediastinal disorders: Differentiation syndrome, like retinoic acid syndrome, has been reported with the use of arsenic trioxide for the treatment of malignancies other than APL.Ear and labyrinth disorders: DeafnessNeoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinomaSkin and subcutaneous tissue disorders: Toxic epidermal necrolysis

7 Drug Interactions

Drugs That Can Prolong the QT/QTc IntervalConcomitant use of these drugs and arsenic trioxide may increase the risk of serious QT/QTc interval prolongation. Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while 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 AbnormalitiesElectrolyte abnormalities increase the risk of serious QT/QTc interval prolongation. Avoid concomitant administration 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. 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.

8.1 Pregnancy

Risk SummaryBased 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 2-4% and 15-20%, respectively.DataHuman DataOne 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 DataStudies 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 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.

8.2 Lactation

Risk SummaryArsenic trioxide is excreted in human milk. There is no information 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 from arsenic trioxide, discontinue breastfeeding during treatment with arsenic trioxide and for two weeks after the final dose.

8.3 Females And Males Of Reproductive Potential

Pregnancy TestingArsenic trioxide can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment with arsenic trioxide [see Use in Specific Populations (8.1)].ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during and after treatment with arsenic trioxide and for six months after the final dose.MalesAdvise males with female sexual partners of reproductive potential to use effective contraception during and after treatment with arsenic trioxide and for three months after the final dose.InfertilityMalesBased on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, arsenic trioxide may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric 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.

8.5 Geriatric Use

The safety and efficacy of arsenic trioxide as a single agent in older patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Six patients age 65 and above (age range: 65 to 73 years) were treated with arsenic trioxide at the recommended dose. A literature review included an additional 4 patients treated with arsenic trioxide for relapsed or refractory APL with ages ranging from 69 to 72 years. No differences in efficacy and safety were observed by age.

8.6 Patients With Renal Impairment

Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with arsenic trioxide, and a dose reduction may be warranted.The use of arsenic trioxide in patients on dialysis has not been studied.

8.7 Patients With 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 (12.3)]. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with arsenic trioxide for toxicity.

10.1 Manifestations

Manifestations of arsenic trioxide (arsenic trioxide) overdosage include convulsions, muscle weakness, and confusion.

10.2 Management

If symptoms of arsenic trioxide (arsenic trioxide) overdosage develop, the injection should be immediately discontinued and chelation therapy should be considered.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.

11 Description

Arsenic trioxide injection is a sterile injectable solution of arsenic trioxide. The molecular formula of the drug substance in the solid state is As2O3, with a molecular weight of 197.8 and has the following structural formula:Arsenic trioxide injection is available in 10 mL, single-dose vials containing 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 and/or sodium hydroxide to adjust to pH 8. Arsenic trioxide injection is preservative-free. Arsenic trioxide, the active ingredient, is present at a concentration of 2 mg/mL. Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) and hydrochloric acid and/or sodium hydroxide, which is used to adjust the pH to 7.5 - 8.5.

12.1 Mechanism 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.

12.2 Pharmacodynamics

Cardiac ElectrophysiologyA dedicated QTc study was not performed with arsenic trioxide. However, 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.

12.3 Pharmacokinetics

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (AsIII). AsIII is the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (AsV) a product of AsIIIoxidation. The pharmacokinetics of arsenical species ([AsIII], [AsV], [MMAV], [DMAV]) 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 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. Peak plasma concentrations of arsenious acid (AsIII), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of AsIII 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 AsIII (mean AUC0-24) 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, MMAV and DMAV, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does AsIII. The mean estimated terminal elimination half-lives of the metabolites MMAV and DMAV 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. AsV is present in plasma only at relatively low levels.DistributionThe volume of distribution (Vss) for AsIII is large (mean 562 L, N=10) indicating that AsIII is widely distributed throughout body tissues. Vss is also dependent on body weight and increases as body weight increases.EliminationMetabolismMuch of the AsIII is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by methyltransferases primarily in the liver. The 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.ExcretionApproximately 15% of the administered arsenic trioxide dose is excreted in the urine as unchanged AsIII. The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine. The total clearance of AsIII 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 7-32 mg.Specific PopulationsPatients with Renal ImpairmentThe effect of renal impairment on the pharmacokinetics of AsIII, AsV, and the pentavalent metabolites MMAV and DMAV was evaluated in 20 patients with advanced malignancies. Patients were classified as having normal renal function (creatinine clearance [CrCl] > 80 mL/min, n=6), mild renal impairment (CrCl 50-80 mL/min, n=5), moderate renal impairment (CrCl 30-49 mL/min, n=6), or severe renal impairment (CrCl < 30 mL/min, n=3). Following twice-weekly administration of 0.15 mg/kg over a 2-hour infusion, the mean AUC0-∞ for AsIII was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC0-∞ for AsIII was approximately 48% higher than that in the normal group.Systemic exposure to MMAV and DMAV tended to be larger in patients with renal impairment; however, the clinical consequences of this increased exposure are not known. AsV plasma levels were generally below the limit of assay quantitation in patients with impaired renal function [see Use in Specific Populations (8.6)]. The use of arsenic trioxide in patients on dialysis has not been studied.Patients with Hepatic ImpairmentThe effect of pharmacokinetics of AsIII, AsV, and the pentavalent metabolites MMAV and DMAV was evaluated following administration of 0.25-0.50 mg/kg of arsenic trioxide in patients with hepatocellular carcinoma. Patients were classified as having normal hepatic function (n=4), mild hepatic impairment (Child-Pugh class A, n=12), moderate hepatic impairment (Child-Pugh class B, n=3), or severe hepatic impairment (Child-Pugh class C, n=1). No clear trend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC in the mild and moderate hepatic impairment groups. However, the one patient with severe hepatic impairment had mean dose-normalized AUC0‑24 and Cmax values 40% and 70% higher, respectively, than those patients with normal hepatic function. The mean dose-normalized trough plasma levels for both MMAV and DMAV in this severely hepatically impaired patient were 2.2-fold and 4.7-fold higher, respectively, than those in the patients with normal hepatic function [see Use in Specific Populations (8.7)].Pediatric PatientsFollowing IV administration of 0.15 mg/kg/day of arsenic trioxide in 10 APL patients (median age = 13.5 years, range 4-20 years), the daily exposure to AsIII (mean AUC0-24h) was 317 ng·hr/mL on Day 1 of Cycle 1 [see Use in Specific Populations (8.4)].Drug Interaction StudiesNo formal assessments of pharmacokinetic drug-drug interactions between arsenic trioxide and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes. In vitro incubation of arsenic trioxide with human liver microsomes showed no inhibitory activity on substrates of the major cytochrome P450 (CYP) enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11. The pharmacokinetics of drugs that are substrates for these CYP enzymes are not expected to be affected by concomitant treatment with arsenic trioxide.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with arsenic trioxide by intravenous administration [see Warnings and Precautions (5.6)].Arsenic trioxide and trivalent arsenite salts have not been demonstrated to be mutagenic to bacteria, yeast, or mammalian cells. Arsenite salts are clastogenic in vitro (human fibroblast, human lymphocytes, Chinese hamster ovary cells, Chinese hamster V79 lung cells). Trivalent arsenic was genotoxic in the chromosome aberrations assay and micronucleus bone marrow assay in mice.The effect of arsenic on fertility has not been adequately studied in humans. Decreased testicular weight and impaired spermatogenesis have been reported in animal studies. Male Wistar rat pups were administered 1.5 mg/kg sodium arsenite solution via the intraperitoneal route from postnatal days 1 to 14 and testes were collected for evaluation on postnatal days 15, 21, and 50. Results of this study revealed an altered morphology of the seminiferous tubules along with degeneration of spermatogenic cells, increased number of sperm with abnormal morphology, and decreased sperm counts. In beagle dogs administered intravenous arsenic trioxide for 90 days, reduced inner cell layers within seminiferous tubules and significantly decreased numbers of spermatocytes, spermatozoa, and sperm cells were observed at doses of 1 mg/kg/day and higher.  The 1 mg/kg/day dose is approximately 3 times the recommended human daily dose on a mg/m2 basis.

14.2 Relapsed Or Refractory Apl

Arsenic trioxide has been investigated in Study PLRXAS01, an open-label, single-arm trial in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen. Patients received arsenic trioxide 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or up to a maximum of 60 days. The CR (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells with a confirmatory bone marrow ≥ 30 days later) rate in this population of previously treated patients was 28 of 40 (70%). Among the 22 patients who had relapsed less than one year after treatment with tretinoin, there were 18 complete responders (82%). Of the 18 patients receiving arsenic trioxide ≥ one year from tretinoin treatment, there were 10 complete responders (55%). The median time to bone marrow remission was 44 days and to onset of CR was 53 days. Three of 5 children, 5 years or older, achieved CR. No children less than 5 years old were treated.Three to six weeks following bone marrow remission, 31 patients received consolidation therapy with arsenic trioxide, at the same dose, for 25 additional days over a period up to 5 weeks. In follow-up treatment, 18 patients received further arsenic trioxide as a maintenance course. Fifteen patients had bone marrow transplants. At last follow-up, 27 of 40 patients were alive with a median follow-up time of 484 days (range 280 to 755) and 23 of 40 patients remained in complete response with a median follow-up time of 483 days (range 280 to 755).Cytogenetic conversion to no detection of the APL chromosome rearrangement was observed in 24 of 28 (86%) patients who met the response criteria defined above, in 5 of 5 (100%) patients who met some, but not all, of the response criteria, and 3 of 7 (43%) of patients who did not respond. RT-PCR conversions to no detection of the APL gene rearrangement were demonstrated in 22 of 28 (79%) of patients who met the response criteria, in 3 of 5 (60%) of patients who met some, but not all, of the response criteria, and in 2 of 7 (29%) of patients who did not respond.Responses were seen across all age groups tested, ranging from 6 to 72 years. The ability to achieve a CR was similar for both genders. There were insufficient patients of Black, Hispanic, or Asian derivation to estimate relative response rates in these groups, but responses were seen in members of each group.

15 References

  • "Hazardous Drugs", OSHA. [Accessed on February 12, 2015 from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

16.1 How Supplied

Arsenic trioxide injection is supplied as a sterile, clear, colorless solution in 10 mL glass, single-dose vials. NDC Strength Pack Style 49315-007-10 12 mg/6 mL (2 mg/mL) single-dose vials 10 vials per carton

16.2 Storage And Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). Do not freeze.Arsenic trioxide is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

17 Patient Counseling Information

  • Differentiation SyndromeAdvise 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.ECG Abnormalities – QT ProlongationAdvise patients that arsenic trioxide may cause ECG abnormalities, including QT prolongation. QT prolongation is an increase in the time it takes the heart to relax between beats. 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 coadministered with other medications that can cause QT prolongation or lead to electrolyte abnormalities.  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. 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.Other Side EffectsAdvise 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. These adverse reactions have not been observed to be permanent or irreversible, nor do they usually require interruption of therapy. Advise patients to call their physician at the onset of any treatment-related adverse reactions.Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].Advise females and males of reproductive potential to use effective contraception during treatment with arsenic trioxide. Advise females to use effective contraception for six months and males to use effective contraception for three months after completing treatment with arsenic trioxide [see Use in Specific Populations (8.3)].Potential Effect on Male FertilityAdvise male patients of the potential risk to future fertility following treatment with arsenic trioxide, as decreased testicular weight and impaired spermatogenesis have been reported in animal studies.LactationAdvise females to discontinue breastfeeding during treatment with arsenic trioxide and for two weeks after treatment with arsenic trioxide [see Use in Specific Populations (8.2)].

Other

Rx onlyManufactured by:Alidac Pharmaceuticals Limited.Ahmedabad, IndiaRev.: 07/19

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