HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedArsenic Trioxide Injection is supplied as sterile, clear, colorless solution in 10 mL glass, single-dose vials. NDC 14789600-10 10 mg/10 mL (1 mg/mL) vial in packages of ten vials.. Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [See USP Controlled Room Temperature]. Do not freeze.Arsenic Trioxide Injection is hazardous drug. Follow applicable special handling and disposal procedures.1.

ADVERSE REACTIONS SECTION.


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)]. 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)]. 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 at safety.nexuspharmalambda-cro.com or 1-855-642-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Newly-Diagnosed Low-Risk APLThe safety of Arsenic Trioxide Injection in combination with tretinoin was evaluated in Study APL0406, randomized trial comparing Arsenic Trioxide Injection plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL [see Clinical Studies (14.1)]. In the Arsenic Trioxide Injection/tretinoin group, 98% of patients completed induction therapy and 89% completed at least three consolidation cycles. In the chemotherapy/tretinoin group, 96% completed induction therapy and 87% patients completed all three courses of consolidation therapy.Serious adverse reactions were reported in 25% of patients on the Arsenic Trioxide Injection/tretinoin arm and 24% on the chemotherapy/tretinoin arm. The serious adverse reactions reported in >= 2% of patients who received Arsenic Trioxide Injection/tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections. Fatal adverse reactions were reported in (1%) patient on the Arsenic Trioxide Injection/tretinoin arm and (6%) patients on the chemotherapy/tretinoin arm.Arsenic Trioxide Injection/tretinoin was discontinued due to toxicity in patient during induction and in patients during the first three consolidation courses, whereas chemotherapy/tretinoin was discontinued due to toxicity in patients during induction and in patients during consolidation.Selected hematologic and nonhematologic toxicities that occurred during induction or consolidation are presented in Table 4.Table 4: Select Adverse Reactions of Arsenic Trioxide Injection in Combination with Tretinoin in Patients with Newly-Diagnosed APL in Study APL0406Mostly cases of reversible peripheral neuropathyAdverse ReactionInduction (%)FirstConsolidation (%)SecondConsolidation (%)ThirdConsolidation (%)Thrombocytopenia 15 days (Grade 3-4) Arsenic Trioxide Injection 74 (58%) (5%) (5%) (7%) /tretinoin Chemotherapy/tretinoin120 (88%)17 (14%)77 (63%)26 (22%)Neutropenia >15 days (Grade 3-4) Arsenic Trioxide Injection 61 (48%) (7%) (6%) (4%) /tretinoin Chemotherapy/tretinoin109 (80%)40 (32%)90 (73%)28 (24%)Hepatic toxicity (Grade 3-4) Arsenic Trioxide Injection 51 (40%) (4%) (1%) (0%) /tretinoin Chemotherapy/tretinoin4 (3%)1 (1%)0 (0%)0 (0%)Infection and fever of unknown origin Arsenic Trioxide Injection 30 (23%) 10 (8%) (3%) (2%) /tretinoin Chemotherapy/tretinoin75 (55%)8 (6%)46 (38%)2 (2%)Hypertriglyceridemia Arsenic Trioxide Injection 29 (22%) 22 (18%) 17 (14%) 16 (14%) /tretinoin Chemotherapy/tretinoin29 (22%)19 (15%)10 (8%)13 (11%)Hypercholesterolemia Arsenic Trioxide Injection 14 (10%) 19 (16%) 19 (16%) 16 (14%) /tretinoin Chemotherapy/tretinoin12 (9%)12 (10%)12 (10%)11 (9%)QT prolongation Arsenic Trioxide Injection 11 (9%) (2%) (2%) (2%) /tretinoin Chemotherapy/tretinoin1 (1%)0 (0%)0 (0%)0 (0%)Gastrointestinal toxicity (Grade 3-4) Arsenic Trioxide Injection (2%) 0(0%) (0%) (0%) /tretinoin Chemotherapy/tretinoin25 (18%)1(1%)6 (5%)0 (0%)Neurotoxicity Arsenic Trioxide Injection (1%) (4%) (5%) (6%) /tretinoin Chemotherapy/tretinoin0 (0%)0 (0%)0 (0%)0 (0%)Cardiac function (Grade 3-4) Arsenic Trioxide Injection (0%) (0%) (0%) (0%) /tretinoin Chemotherapy/tretinoin5 (4%)0 (0%)0 (0%)0 (0%)Relapsed or Refractory APLSafety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of Arsenic Trioxide Injection. 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, 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 describes the adverse reactions in patients aged to 73 years with APL who received Arsenic Trioxide Injection at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received Arsenic Trioxide Injection.Table 5: Adverse Reactions (>= 5%) in Patients with Relapsed or Refractory APL Who Received Arsenic Trioxide Injection in Study PLRXAS01Body SystemAdverse reactionAny Grade Adverse ReactionsGrade >= Adverse Reactionsn%n%Gastrointestinal disorders Nausea3075 Abdominal pain (lower upper)2358410 Vomiting2358 Diarrhea2153 Sore throat1435 Constipation112813 Anorexia923 Appetite decreased615 Loose stools410 Dyspepsia410 Oral blistering38 Fecal incontinence38 Gastrointestinal hemorrhage38 Dry mouth38 Abdominal tenderness38 Diarrhea hemorrhagic38 Abdominal distension38Respiratory Cough2665 Dyspnea2153410 Epistaxis1025 Hypoxia923410 Pleural effusion82013 Post nasal drip513 Wheezing513 Decreased breath sounds410 Crepitations410 Rales410 Hemoptysis38 Tachypnea38 Rhonchi38General disorders and administration site conditions Fatigue256325 Pyrexia (fever)256325 Edema non-specific1640 Rigors1538 Chest pain102525 Injection site pain820 Pain non-specific61513 Injection site erythema513General disorders and administration site conditions (Continued) Weight gain513 Injection site edema410 Weakness41025 Hemorrhage38 Weight loss38 Drug hypersensitivity2513Nervous system disorders Headache246013 Insomnia174313 Paresthesia133325 Dizziness (excluding vertigo)923 Tremor513 Convulsion3825 Somnolence38 Coma2525Cardiac disorders Tachycardia2255 ECG QT corrected interval prolonged 500 msec1640 Palpitations410 ECG abnormal other than QT interval prolongation38Metabolism and nutrition disordersHypokalemia2050513Hypomagnesemia1845513Hyperglycemia1845513ALT increased82025Hyperkalemia71825AST increased51313Hypocalcemia410Hypoglycemia38Acidosis25Hematologic disorders Leukocytosis205013 Anemia82025 Thrombocytopenia718513 Febrile neutropenia51338 Neutropenia410410 Disseminated intravascular coagulation3838 Lymphadenopathy38Skin and subcutaneous tissue disorders Dermatitis1743 Pruritus133313 Ecchymosis820 Dry skin615 Erythema non-specific513 Increased sweating513 Facial edema38 Night sweats38 Petechiae38 Hyperpigmentation38 Non-specific skin lesions38 Urticaria38 Local exfoliation25 Eyelid edema25Musculoskeletal, connective tissue, and bone disorders Arthralgia133338 Myalgia102525 Bone pain923410 Back pain71813 Neck pain513 Pain in limb51325Psychiatric disorders Anxiety1230 Depression820 Agitation25 Confusion25Vascular disorders Hypotension102525 Flushing410 Hypertension410 Pallor410Infections and infestations Sinusitis820 Herpes simplex513 Upper respiratory tract infection51313 Bacterial infection non-specific3813 Herpes zoster38 Nasopharyngitis25 Oral candidiasis25 Sepsis2525Reproductive system disorders Vaginal hemorrhage513 Intermenstrual bleeding38Ocular disorders Eye irritation410 Blurred vision410 Dry eye38 Painful red eye25Renal and urinary disorders Renal failure3813 Renal impairment38 Oliguria25 Incontinence25Ear disorders Earache38 Tinnitus25. Other Clinically Relevant Adverse Reactions. LeukocytosisArsenic Trioxide Injection can induce proliferation of leukemic promyelocytes resulting in rapid increase in white blood cell count. Leukocytosis greater than 10 Gi/L developed during induction therapy in 43% patients receiving Arsenic Trioxide Injection/tretinoin for newlydiagnosed low-risk APL and in 50% of patients receiving Arsenic Trioxide Injection monotherapy for relapsed/refractory APL. In the relapsed/refractory setting, relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Arsenic Trioxide Injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate the frequency or establish causal relationship to drug exposure.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 failureEar and labyrinth disorders: DeafnessHematologic disorders: Pancytopenia, bone marrow necrosisInfections: Herpes zosterInvestigations: Gamma-glutamyltransferase increasedMusculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysisNeoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinomaNervous system disorders: Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernickes encephalopathy, posterior reversible encephalopathy syndromeSkin and subcutaneous tissue disorders: Toxic epidermal necrolysis.

BOXED WARNING SECTION.


WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKES. Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection 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 multiorgan 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 Injection 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 Injection to patients with 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 Wernickes, has occurred with Arsenic Trioxide Injection. Wernickes is neurologic emergency. Consider testing thiamine levels in patients with or at risk for thiamine deficiency. Monitor patients neurological symptoms and nutritional status while receiving Arsenic Trioxide Injection 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 WERNICKESSee full prescribing information for complete boxed warning.Patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection have experienced symptoms of differentiation syndrome, which may be life-threatening or fatal. If differentiation syndrome is suspected, immediately initiate highdose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold Arsenic Trioxide Injection. (2.3, 5.1)Arsenic Trioxide Injection 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 Injection to patients with ventricular arrhythmia or prolonged QTc interval. Withhold Arsenic Trioxide Injection until resolution and resume at reduced dose for QTc prolongation. (2.3, 5.2)Serious encephalopathy, including Wernickes, has occurred with Arsenic Trioxide Injection. If Wernickes encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. (5.3). Patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection have experienced symptoms of differentiation syndrome, which may be life-threatening or fatal. If differentiation syndrome is suspected, immediately initiate highdose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold Arsenic Trioxide Injection. (2.3, 5.1). Arsenic Trioxide Injection 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 Injection to patients with ventricular arrhythmia or prolonged QTc interval. Withhold Arsenic Trioxide Injection until resolution and resume at reduced dose for QTc prolongation. (2.3, 5.2). Serious encephalopathy, including Wernickes, has occurred with Arsenic Trioxide Injection. If Wernickes encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. (5.3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with Arsenic Trioxide Injection 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 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 mg/kg/day and higher. The mg/kg/day dose is approximately times the recommended human daily dose on mg/m2 basis.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of Arsenic Trioxide Injection 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 ElectrophysiologyIn single-arm trial of Arsenic Trioxide Injection (0.15 mg/kg daily), 16 of 40 patients (40%) had QTc interval greater than 500 msec. Prolongation of the QTc was observed between and weeks after Arsenic Trioxide Injection infusion, and then returned towards baseline by the end of weeks after Arsenic Trioxide Injection 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) product of AsIII oxidation.The pharmacokinetics of arsenical species ([AsIII], [AsV], [MMAV], [DMAV]) were determined in APL patients following once-daily doses of 0.15 mg/kg for days per week. Over the total single-dose range of 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 biphasic manner with mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by slower terminal elimination phase. The daily exposure to AsIII (mean AUC0-24h) was 194 ng.hr/mL (n=5) on Day of Cycle 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.. Elimination. MetabolismMuch 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 Injection 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 L/h. Clearance is not dependent on body weight or dose administered over the range of 7-32 mg.. Specific Populations. Patients 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 [CLcr] 80 mL/min, n=6), mild renal impairment (CLcr 50-80 mL/min, n=5), moderate renal impairment (CLcr 30-49 mL/min, n=6), or severe renal impairment (CLcr 30 mL/min, n=3). Following twice-weekly administration of 0.15 mg/kg over 2-hour infusion, the mean AUC0-INF for AsIII was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC0-INF 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 AUC0-24h 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 intravenous 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 of Cycle [see Use in Specific Populations (8.4)]. Drug Interaction StudiesNo formal assessments of pharmacokinetic drug-drug interactions between Arsenic Trioxide Injection 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.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Newly-Diagnosed Low-Risk APL. Arsenic Trioxide Injection in combination with tretinoin was investigated in Study APL0406 (NCT00482833), multicenter, randomized, open-label trial in patients with newly-diagnosed low-risk APL (white blood cell count at diagnosis <=10 Gi/L). The patients were randomized 1:1 to receive Arsenic Trioxide Injection/tretinoin for induction and consolidation or chemotherapy/tretinoin for induction, consolidation, and maintenance.Patients in the Arsenic Trioxide Injection/tretinoin group received induction treatment with Arsenic Trioxide Injection 0.15 mg/kg intravenously once daily in combination with tretinoin 22.5 mg/m2 (rounded to the nearest 10 mg increment) orally twice daily until hematologic complete remission (CR) or for maximum of 60 days. Patients in this group who achieved CR during induction received four 8-week cycles of consolidation treatment with Arsenic Trioxide Injection 0.15 mg/kg intravenously once daily for days every week during weeks 1-4 of the 8-week cycle, in combination with tretinoin 22.5 mg/m2 (rounded to the nearest 10 mg increment) orally twice daily during weeks 1-2 and 5-6 of the 8-week cycle. Tretinoin was omitted during weeks 5-6 of the last cycle.Patients in the chemotherapy/tretinoin group received idarubicin 12 mg/m2 intravenously once daily on days 2, 4, 6, and in combination with tretinoin 22.5 mg/m2 (rounded to the nearest 10 mg increment) orally twice daily, starting on day 1, until hematologic CR or for maximum of 60 days. Patients in this group who achieved CR during induction received consolidation and maintenance treatment with tretinoin in combination with chemotherapy.The trial enrolled 162 patients with morphologic diagnosis of APL. The median age of patients was 45 years in the Arsenic Trioxide Injection/tretinoin arm and 47 years in the chemotherapy/tretinoin arm, and 52% and 46% were male in the Arsenic Trioxide Injection/tretinoin and chemotherapy/tretinoin arms, respectively. Baseline characteristics were balanced between treatment arms, including median WBC count, platelet count, PML-RARA isoform, and FLT3-ITD status.Efficacy was based on event-free survival (EFS) rate at years. EFS was defined as the time from randomization to the occurrence of treatment failure, defined as no achievement of CR or CRi after induction therapy, no achievement of molecular remission after consolidation courses, molecular relapse, hematologic relapse, or death. The primary analysis of EFS was based on the difference between the two treatment arms in patients achieving EFS at years. With median follow-up of 34.4 months, the year EFS rate of the modified ITT (mITT) population (patients who received at least one dose of the assigned treatment) was 94% in the Arsenic Trioxide Injection/tretinoin arm (n=77) versus 82% in the chemotherapy/tretinoin arm (n=79), treatment difference of 11% (95% CI: 1, 22; p-value 0.048).Overall survival (OS) for the mITT population was 99% (95% CI: 93, 100) in the Arsenic Trioxide Injection/tretinoin arm versus 91% (95% CI: 86, 97) in the chemotherapy/tretinoin arm. The difference in 2-year OS rate between the arms was 8% (95% CI: 0, 16).Figure 1: Event-Free Survival for Newly-Diagnosed APL The number of patients in the plot is based on the mITT population.. Figure 1. 14.2 Relapsed or Refractory APL. Arsenic Trioxide Injection was investigated in Study PLRXAS01, an open-label, single-arm trial in 40 patients with relapsed or refractory APL who were previously treated with an anthracycline and retinoid regimen. Patients received Arsenic Trioxide Injection 0.15 mg/kg/day intravenously over to hours until the bone marrow was cleared of leukemic cells or for maximum of 60 days. The CR (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells with 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 Injection >= 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 children, years or older, achieved CR. No children less than years old were treated.Three to six weeks following bone marrow remission, 31 patients received consolidation therapy with Arsenic Trioxide Injection, at the same dose, for 25 additional days over period up to weeks. In follow-up treatment, 18 patients received further Arsenic Trioxide Injection as maintenance course. Fifteen patients had bone marrow transplants. At last follow-up, 27 of 40 patients were alive with median follow-up time of 484 days (range 280 to 755) and 23 of 40 patients remained in complete response with 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 of (100%) patients who met some, but not all, of the response criteria, and of (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 of (60%) of patients who met some, but not all, of the response criteria, and in of (29%) of patients who did not respond. Responses were seen across all age groups tested, ranging from to 72 years. The ability to achieve CR was similar for both sexes. There were insufficient patients of Black, Hispanic, or Asian ancestry to estimate relative response rates in these groups, but responses were seen in each group.

CLINICAL TRIALS EXPERIENCE SECTION.


6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Newly-Diagnosed Low-Risk APLThe safety of Arsenic Trioxide Injection in combination with tretinoin was evaluated in Study APL0406, randomized trial comparing Arsenic Trioxide Injection plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL [see Clinical Studies (14.1)]. In the Arsenic Trioxide Injection/tretinoin group, 98% of patients completed induction therapy and 89% completed at least three consolidation cycles. In the chemotherapy/tretinoin group, 96% completed induction therapy and 87% patients completed all three courses of consolidation therapy.Serious adverse reactions were reported in 25% of patients on the Arsenic Trioxide Injection/tretinoin arm and 24% on the chemotherapy/tretinoin arm. The serious adverse reactions reported in >= 2% of patients who received Arsenic Trioxide Injection/tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections. Fatal adverse reactions were reported in (1%) patient on the Arsenic Trioxide Injection/tretinoin arm and (6%) patients on the chemotherapy/tretinoin arm.Arsenic Trioxide Injection/tretinoin was discontinued due to toxicity in patient during induction and in patients during the first three consolidation courses, whereas chemotherapy/tretinoin was discontinued due to toxicity in patients during induction and in patients during consolidation.Selected hematologic and nonhematologic toxicities that occurred during induction or consolidation are presented in Table 4.Table 4: Select Adverse Reactions of Arsenic Trioxide Injection in Combination with Tretinoin in Patients with Newly-Diagnosed APL in Study APL0406Mostly cases of reversible peripheral neuropathyAdverse ReactionInduction (%)FirstConsolidation (%)SecondConsolidation (%)ThirdConsolidation (%)Thrombocytopenia 15 days (Grade 3-4) Arsenic Trioxide Injection 74 (58%) (5%) (5%) (7%) /tretinoin Chemotherapy/tretinoin120 (88%)17 (14%)77 (63%)26 (22%)Neutropenia >15 days (Grade 3-4) Arsenic Trioxide Injection 61 (48%) (7%) (6%) (4%) /tretinoin Chemotherapy/tretinoin109 (80%)40 (32%)90 (73%)28 (24%)Hepatic toxicity (Grade 3-4) Arsenic Trioxide Injection 51 (40%) (4%) (1%) (0%) /tretinoin Chemotherapy/tretinoin4 (3%)1 (1%)0 (0%)0 (0%)Infection and fever of unknown origin Arsenic Trioxide Injection 30 (23%) 10 (8%) (3%) (2%) /tretinoin Chemotherapy/tretinoin75 (55%)8 (6%)46 (38%)2 (2%)Hypertriglyceridemia Arsenic Trioxide Injection 29 (22%) 22 (18%) 17 (14%) 16 (14%) /tretinoin Chemotherapy/tretinoin29 (22%)19 (15%)10 (8%)13 (11%)Hypercholesterolemia Arsenic Trioxide Injection 14 (10%) 19 (16%) 19 (16%) 16 (14%) /tretinoin Chemotherapy/tretinoin12 (9%)12 (10%)12 (10%)11 (9%)QT prolongation Arsenic Trioxide Injection 11 (9%) (2%) (2%) (2%) /tretinoin Chemotherapy/tretinoin1 (1%)0 (0%)0 (0%)0 (0%)Gastrointestinal toxicity (Grade 3-4) Arsenic Trioxide Injection (2%) 0(0%) (0%) (0%) /tretinoin Chemotherapy/tretinoin25 (18%)1(1%)6 (5%)0 (0%)Neurotoxicity Arsenic Trioxide Injection (1%) (4%) (5%) (6%) /tretinoin Chemotherapy/tretinoin0 (0%)0 (0%)0 (0%)0 (0%)Cardiac function (Grade 3-4) Arsenic Trioxide Injection (0%) (0%) (0%) (0%) /tretinoin Chemotherapy/tretinoin5 (4%)0 (0%)0 (0%)0 (0%)Relapsed or Refractory APLSafety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of Arsenic Trioxide Injection. 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, 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 describes the adverse reactions in patients aged to 73 years with APL who received Arsenic Trioxide Injection at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received Arsenic Trioxide Injection.Table 5: Adverse Reactions (>= 5%) in Patients with Relapsed or Refractory APL Who Received Arsenic Trioxide Injection in Study PLRXAS01Body SystemAdverse reactionAny Grade Adverse ReactionsGrade >= Adverse Reactionsn%n%Gastrointestinal disorders Nausea3075 Abdominal pain (lower upper)2358410 Vomiting2358 Diarrhea2153 Sore throat1435 Constipation112813 Anorexia923 Appetite decreased615 Loose stools410 Dyspepsia410 Oral blistering38 Fecal incontinence38 Gastrointestinal hemorrhage38 Dry mouth38 Abdominal tenderness38 Diarrhea hemorrhagic38 Abdominal distension38Respiratory Cough2665 Dyspnea2153410 Epistaxis1025 Hypoxia923410 Pleural effusion82013 Post nasal drip513 Wheezing513 Decreased breath sounds410 Crepitations410 Rales410 Hemoptysis38 Tachypnea38 Rhonchi38General disorders and administration site conditions Fatigue256325 Pyrexia (fever)256325 Edema non-specific1640 Rigors1538 Chest pain102525 Injection site pain820 Pain non-specific61513 Injection site erythema513General disorders and administration site conditions (Continued) Weight gain513 Injection site edema410 Weakness41025 Hemorrhage38 Weight loss38 Drug hypersensitivity2513Nervous system disorders Headache246013 Insomnia174313 Paresthesia133325 Dizziness (excluding vertigo)923 Tremor513 Convulsion3825 Somnolence38 Coma2525Cardiac disorders Tachycardia2255 ECG QT corrected interval prolonged 500 msec1640 Palpitations410 ECG abnormal other than QT interval prolongation38Metabolism and nutrition disordersHypokalemia2050513Hypomagnesemia1845513Hyperglycemia1845513ALT increased82025Hyperkalemia71825AST increased51313Hypocalcemia410Hypoglycemia38Acidosis25Hematologic disorders Leukocytosis205013 Anemia82025 Thrombocytopenia718513 Febrile neutropenia51338 Neutropenia410410 Disseminated intravascular coagulation3838 Lymphadenopathy38Skin and subcutaneous tissue disorders Dermatitis1743 Pruritus133313 Ecchymosis820 Dry skin615 Erythema non-specific513 Increased sweating513 Facial edema38 Night sweats38 Petechiae38 Hyperpigmentation38 Non-specific skin lesions38 Urticaria38 Local exfoliation25 Eyelid edema25Musculoskeletal, connective tissue, and bone disorders Arthralgia133338 Myalgia102525 Bone pain923410 Back pain71813 Neck pain513 Pain in limb51325Psychiatric disorders Anxiety1230 Depression820 Agitation25 Confusion25Vascular disorders Hypotension102525 Flushing410 Hypertension410 Pallor410Infections and infestations Sinusitis820 Herpes simplex513 Upper respiratory tract infection51313 Bacterial infection non-specific3813 Herpes zoster38 Nasopharyngitis25 Oral candidiasis25 Sepsis2525Reproductive system disorders Vaginal hemorrhage513 Intermenstrual bleeding38Ocular disorders Eye irritation410 Blurred vision410 Dry eye38 Painful red eye25Renal and urinary disorders Renal failure3813 Renal impairment38 Oliguria25 Incontinence25Ear disorders Earache38 Tinnitus25. Other Clinically Relevant Adverse Reactions. LeukocytosisArsenic Trioxide Injection can induce proliferation of leukemic promyelocytes resulting in rapid increase in white blood cell count. Leukocytosis greater than 10 Gi/L developed during induction therapy in 43% patients receiving Arsenic Trioxide Injection/tretinoin for newlydiagnosed low-risk APL and in 50% of patients receiving Arsenic Trioxide Injection monotherapy for relapsed/refractory APL. In the relapsed/refractory setting, relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Arsenic Trioxide Injection is contraindicated in patients with hypersensitivity to arsenic.. Hypersensitivity to arsenic. (4).

DESCRIPTION SECTION.


11 DESCRIPTION. Arsenic Trioxide Injection is sterile injectable solution of arsenic trioxide. The molecular formula of arsenic trioxide in the solid state is As2O3, with 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 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 concentration of 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.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Newly-diagnosed low-risk APL:Induction: Administer 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission. Do not exceed 60 days. (2.1)Consolidation: 0.15 mg/kg intravenously daily days per week during weeks 1-4 of an 8-week cycle for total of cycles in combination with tretinoin. (2.1)Relapsed or refractory APL:Induction: 0.15 mg/kg intravenously daily until bone marrow remission. Do not exceed 60 days. (2.2)Consolidation: 0.15 mg/kg intravenously daily for 25 doses over period up to weeks. (2.2). Induction: Administer 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission. Do not exceed 60 days. (2.1). Consolidation: 0.15 mg/kg intravenously daily days per week during weeks 1-4 of an 8-week cycle for total of cycles in combination with tretinoin. (2.1). Induction: 0.15 mg/kg intravenously daily until bone marrow remission. Do not exceed 60 days. (2.2). Consolidation: 0.15 mg/kg intravenously daily for 25 doses over period up to weeks. (2.2). 2.1 Recommended Dosage for Newly-Diagnosed Low-Risk Acute Promyelocytic Leukemia (APL). treatment course for patients with newly-diagnosed low-risk APL consists of induction cycle and consolidation cycles.For the induction cycle, the recommended dosage of Arsenic Trioxide Injection is 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission but not to exceed 60 days (see Table 1).For the consolidation cycles, the recommended dosage of Arsenic Trioxide Injection is 0.15 mg/kg/day intravenously daily days per week during weeks 1-4 of each 8-week cycle for total of cycles in combination with tretinoin (see Table 1). Omit tretinoin during weeks 5-6 of the fourth cycle of consolidation.Table 1: Recommended Dosage of Arsenic Trioxide Injection in Combination with TretinoinInduction (1 cycle)Arsenic Trioxide Injection0.15 mg/kg once daily intravenouslyuntil marrow remission but not to exceed 60 daysTretinoina 22.5 mg/m2 twice daily orallyuntil marrow remission but not to exceed 60 daysaRounded to the nearest 10 mg incrementbOmitted during the 4th cycle of consolidationConsolidation (4 cycles)Week 1Week 2Week 3Week 4Week 5Week 6Week 7Week 8Arsenic Trioxide Injection0.15 mg/kg once daily intravenouslyDays 1-5Days 1-5Days 1-5Days 1-5--------Tretinoina 22.5 mg/m2 twice daily orallyDays 1-7Days 1-7----Daysb 1-7Daysb 1-7----Differentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day until the end of induction cycle with Arsenic Trioxide Injection and tretinoin is recommended.. For the induction cycle, the recommended dosage of Arsenic Trioxide Injection is 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission but not to exceed 60 days (see Table 1).. For the consolidation cycles, the recommended dosage of Arsenic Trioxide Injection is 0.15 mg/kg/day intravenously daily days per week during weeks 1-4 of each 8-week cycle for total of cycles in combination with tretinoin (see Table 1). Omit tretinoin during weeks 5-6 of the fourth cycle of consolidation.. 2.2 Recommended Dosage for Relapsed or Refractory APL. treatment course for patients with relapsed or refractory APL consists of induction cycle and 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 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 period of up to weeks. Begin consolidation to weeks after completion of induction cycle.. 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 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 period of up to weeks. Begin consolidation to weeks after completion of induction cycle.. 2.3 Monitoring and Dosage Modifications for Adverse Reactions. During induction, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly.Table shows the dosage modifications for adverse reactions due to Arsenic Trioxide Injection when used alone or in combination with tretinoin.Table 2: Dosage Modifications for Adverse Reactions of Arsenic Trioxide InjectionAdverse ReactionDosage ModificationDifferentiation syndrome, defined by the presence of or more of the following: -Unexplained fever-Dyspnea-Pleural and/or pericardial effusion-Pulmonary infiltrates-Renal Failure-Hypotension-Weight gain greater than kg [see Warnings and Precautions (5.1)] Temporarily withhold Arsenic Trioxide Injection. Consider holding tretinoin if symptoms are severe.Administer dexamethasone 10 mg intravenously every 12 hours until the resolution of signs and symptoms for minimum of 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 and/or tretinoin to the previous dose.QTc (Framingham formula)Prolongation greater than 450 msec for men or greater than460 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 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 [see Dosage and Administration (2.1)].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 or more of the following: -Total bilirubin (TB) greater than times the upper limit of normal (ULN)-Aspartate aminotransferase (AST) greater than times the (ULN)-Alkaline phosphatase (AP) greater than times the ULN [see Warnings and Precautions (5.4)] Withhold Arsenic Trioxide Injection and/or tretinoin.Resume treatment at 50% reduced dose of the withheld drug(s) when TB is less than 1.5 times the ULN and AP/AST are less than 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 3-4) nonhematologic reactions [see Adverse Reactions (6)] Temporarily withhold Arsenic Trioxide Injection and tretinoin.When the adverse reaction resolves to no more than mild (grade 1), resume Arsenic Trioxide Injection and tretinoin reduced by dose levels (see Table below).Moderate (grade 2) nonhematologic reactions [see Adverse Reactions (6)] Reduce the dose of Arsenic Trioxide Injection and/or tretinoin by dose level (see Table 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 or more of the following: -Absolute neutrophil count less than Gi/L-Platelets less than 50 Gi/L lasting more than weeks [see Adverse Reactions (6)] Consider reducing the dose of Arsenic Trioxide Injection and tretinoin by dose level (see Table below).If myelosuppression lasts >= 50 days or occurs on consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume Arsenic Trioxide Injection and tretinoin at dose level lower (see Table below).Table 3: Dose Reduction Levels for Hematologic and Nonhematologic ToxicitiesRounded to the nearest 10 mg incrementDose LevelArsenic TrioxideInjection mg/kg intravenously once dailyTretinoin mg/m2orallytwice dailyStarting level0.1522.5-10.1118.75-20.1012.5-30.07510. -Unexplained fever. -Dyspnea. -Pleural and/or pericardial effusion. -Pulmonary infiltrates. -Renal Failure. -Hypotension. -Weight gain greater than kg. Temporarily withhold Arsenic Trioxide Injection. Consider holding tretinoin if symptoms are severe.. Administer dexamethasone 10 mg intravenously every 12 hours until the resolution of signs and symptoms for minimum of 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 and/or tretinoin to the previous dose.. 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 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 [see Dosage and Administration (2.1)].. 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.. -Total bilirubin (TB) greater than times the upper limit of normal (ULN). -Aspartate aminotransferase (AST) greater than times the (ULN). -Alkaline phosphatase (AP) greater than times the ULN. Withhold Arsenic Trioxide Injection and/or tretinoin.. Resume treatment at 50% reduced dose of the withheld drug(s) when TB is less than 1.5 times the ULN and AP/AST are less than 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.. Temporarily withhold Arsenic Trioxide Injection and tretinoin.. When the adverse reaction resolves to no more than mild (grade 1), resume Arsenic Trioxide Injection and tretinoin reduced by dose levels (see Table below).. Reduce the dose of Arsenic Trioxide Injection and/or tretinoin by dose level (see Table below).. Administer hydroxyurea.. Hydroxyurea may be discontinued when the WBC declines below 10 Gi/L.. -Absolute neutrophil count less than Gi/L. -Platelets less than 50 Gi/L lasting more than weeks. Consider reducing the dose of Arsenic Trioxide Injection and tretinoin by dose level (see Table below).. If myelosuppression lasts >= 50 days or occurs on consecutive cycles, assess marrow aspirate for remission status. In the case of molecular remission, resume Arsenic Trioxide Injection and tretinoin at dose level lower (see Table below).. 2.4 Preparation and Administration. ReconstitutionDilute 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.. AdministrationParenteral 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 hours. The infusion duration may be extended up to hours if acute vasomotor reactions are observed. 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 ProceduresArsenic Trioxide Injection is hazardous drug. Follow applicable special handling and disposal procedures.1.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Injection: 12 mg/6 mL (2 mg/mL) arsenic trioxide clear solution in single-dose vial.. Injection: 12 mg/6 mL 2 mg/mL) arsenic trioxide in single-dose vial. (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Drugs That Can Prolong the QT/QTc IntervalConcomitant use of these drugs and Arsenic Trioxide Injection 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 Injection. 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 [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 Injection.. Drugs That Can Lead to HepatotoxicityConcomitant use of these drugs and Arsenic Trioxide Injection, particularly when given in combination with tretinoin, 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 Injection. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Use of Arsenic Trioxide Injection in combination with tretinoin in newly-diagnosed adult patients with low-risk APL is supported by randomized, controlled trial that included 16 patients between the ages of 60 and 70 years. No overall differences in safety or effectiveness were observed between these patients and younger patients. literature review included an additional 77 patients aged 60 to 84 years who were treated with arsenic trioxide in combination with tretinoin as part of induction and consolidation therapy for low- and high-risk APL. These studies showed lower survival rates in older patients. Monitor elderly patients frequently during treatment with Arsenic Trioxide Injection.Use of Arsenic Trioxide Injection as monotherapy in patients with relapsed or refractory APL is supported by the open-label, single-arm trial that included patients aged 65 and older (range: 65 to 73 years). literature review included an additional 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.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. Arsenic Trioxide Injection is an arsenical indicated:In combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RARalpha gene expression. (1.1)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). In combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RARalpha gene expression. (1.1). 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). 1.1 Newly-Diagnosed Low-Risk APL. Arsenic Trioxide Injection is indicated in combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.. 1.2 Relapsed 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.

INFORMATION FOR PATIENTS SECTION.


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 [see Warnings and Precautions (5.1)].. Cardiac Conduction AbnormalitiesAdvise patients that Arsenic Trioxide Injection 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 complete list of current medications as caution should be taken when Arsenic Trioxide Injection is coadministered 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 Wernickes 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 Warnings and Precautions (5.3)].Advise patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide) that Wernickes encephalopathy is 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 ToxicityAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of 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 Injection and for 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 Injection for months after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with Arsenic Trioxide Injection and for weeks after the last dose [see Use in Specific Populations (8.2)].. Infertility Other Adverse ReactionsAdvise males of reproductive potential that Arsenic Trioxide Injection may impair fertility [see Use in Specific Population (8.3)].Advise patients of the expected adverse reactions of Arsenic Trioxide Injection. 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)].Manufactured in Germany for:Nexus Pharmaceuticals, Inc., Lincolnshire, Illinois 60069, USACarton NDC 14789-600-10Vial NDC 14789-600-07 Arsenic Trioxide Injection The container closure is not made with natural rubber latex.10 10 mL Vials10 mg/10 mL (1 mg/mL) For Intravenous Use OnlyRx onlyARSPIR002DENEXUSPHARMACEUTICALSRevised by Nexus Pharmaceuticals, Inc. 09/2021.

LACTATION SECTION.


8.2 Lactation. Risk SummaryArsenic 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 breastfed child, advise women not to breastfeed during treatment with Arsenic Trioxide Injection and for weeks after the final dose.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. The mechanism of action of Arsenic Trioxide Injection 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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with Arsenic Trioxide Injection 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 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 mg/kg/day and higher. The mg/kg/day dose is approximately times the recommended human daily dose on mg/m2 basis.

OVERDOSAGE SECTION.


10 OVERDOSAGE. ManifestationsManifestations of Arsenic Trioxide Injection (arsenic trioxide) overdosage include convulsions, muscle weakness, and confusion.. ManagementFor symptoms of Arsenic Trioxide Injection (arsenic trioxide) overdosage, immediately discontinue Arsenic Trioxide Injection and consider chelation therapy.A conventional protocol for acute arsenic intoxication includes dimercaprol administered at dose of mg/kg intramuscularly every hours until immediate life-threatening toxicity has subsided. Thereafter, penicillamine at dose of 250 mg orally, up to maximum frequency of four times per day (<= g per day), may be given.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Principal Display Panel 10 mL Carton LabelNDC 14789-600-10Rx OnlyArsenic TrioxideInjection10 mg/10 mL (1 mg/mL)For Intravenous Infusion OnlyPreservative FreeCytotoxic Agent10 10 mL Single Dose VialNEXUSPHARMACEUTICALS. Principal Display Panel 10 mL Carton Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and efficacy of Arsenic Trioxide Injection in combination with tretinoin in pediatric patients has not been established.The safety and efficacy of Arsenic Trioxide Injection as single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: to 16 years) were treated with Arsenic Trioxide Injection at the recommended dose of 0.15 mg/kg/day. literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from to 21 years. No differences in efficacy and safety were observed by age.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn single-arm trial of Arsenic Trioxide Injection (0.15 mg/kg daily), 16 of 40 patients (40%) had QTc interval greater than 500 msec. Prolongation of the QTc was observed between and weeks after Arsenic Trioxide Injection infusion, and then returned towards baseline by the end of weeks after Arsenic Trioxide Injection infusion.

PHARMACOKINETICS SECTION.


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) product of AsIII oxidation.The pharmacokinetics of arsenical species ([AsIII], [AsV], [MMAV], [DMAV]) were determined in APL patients following once-daily doses of 0.15 mg/kg for days per week. Over the total single-dose range of 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 biphasic manner with mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by slower terminal elimination phase. The daily exposure to AsIII (mean AUC0-24h) was 194 ng.hr/mL (n=5) on Day of Cycle 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.. Elimination. MetabolismMuch 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 Injection 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 L/h. Clearance is not dependent on body weight or dose administered over the range of 7-32 mg.. Specific Populations. Patients 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 [CLcr] 80 mL/min, n=6), mild renal impairment (CLcr 50-80 mL/min, n=5), moderate renal impairment (CLcr 30-49 mL/min, n=6), or severe renal impairment (CLcr 30 mL/min, n=3). Following twice-weekly administration of 0.15 mg/kg over 2-hour infusion, the mean AUC0-INF for AsIII was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC0-INF 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 AUC0-24h 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 intravenous 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 of Cycle [see Use in Specific Populations (8.4)]. Drug Interaction StudiesNo formal assessments of pharmacokinetic drug-drug interactions between Arsenic Trioxide Injection 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.

PREGNANCY SECTION.


8.1 Pregnancy. Risk SummaryBased on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, Arsenic Trioxide Injection can cause fetal harm when administered to pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day at dose approximately 10 times the recommended human daily dose on mg/m2 basis (see Data). related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at dose approximately times the projected human dose on mg/m2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on mg/m2 basis. There are no studies with the use of Arsenic Trioxide Injection in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 DataOne patient was reported to deliver live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have normal pregnancy outcome. third patient was pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had normal pregnancy outcome after treatment and monitoring. fourth patient who became pregnant while receiving arsenic trioxide had 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 (approximately 10 times the recommended human daily dose on mg/m2 basis). Similar findings occurred in mice administered 10 mg/kg dose of related trivalent arsenic, sodium arsenite (approximately times the projected human dose on mg/m2 basis), on gestation days 6, 7, 8, or 9. Intravenous injection of mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on mg/m2 basis) on gestation day (the lowest dose tested) resulted in neural-tube defects in hamsters.

REFERENCES SECTION.


15 REFERENCES. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.


1.1 Newly-Diagnosed Low-Risk APL. Arsenic Trioxide Injection is indicated in combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

STORAGE AND HANDLING SECTION.


Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [See USP Controlled Room Temperature]. Do not freeze.Arsenic Trioxide Injection is hazardous drug. Follow applicable special handling and disposal procedures.1.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed. (8.2)Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with Arsenic Trioxide Injection; 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 Injection. (8.7). Lactation: Advise women not to breastfeed. (8.2). Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with Arsenic Trioxide Injection; 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 Injection. (8.7). 8.1 Pregnancy. Risk SummaryBased on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, Arsenic Trioxide Injection can cause fetal harm when administered to pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day at dose approximately 10 times the recommended human daily dose on mg/m2 basis (see Data). related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at dose approximately times the projected human dose on mg/m2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on mg/m2 basis. There are no studies with the use of Arsenic Trioxide Injection in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 DataOne patient was reported to deliver live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have normal pregnancy outcome. third patient was pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had normal pregnancy outcome after treatment and monitoring. fourth patient who became pregnant while receiving arsenic trioxide had 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 (approximately 10 times the recommended human daily dose on mg/m2 basis). Similar findings occurred in mice administered 10 mg/kg dose of related trivalent arsenic, sodium arsenite (approximately times the projected human dose on mg/m2 basis), on gestation days 6, 7, 8, or 9. Intravenous injection of mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on mg/m2 basis) on gestation day (the lowest dose tested) resulted in neural-tube defects in hamsters.. 8.2 Lactation. Risk SummaryArsenic 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 breastfed child, advise women not to breastfeed during treatment with Arsenic Trioxide Injection and for weeks after the final dose.. 8.3 Females and Males of Reproductive Potential. Arsenic Trioxide Injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingConduct pregnancy testing in females of reproductive potential prior to initiation of Arsenic Trioxide Injection.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for months after the final dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for months after the final dose.. Infertility. MalesBased on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, Arsenic Trioxide Injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and efficacy of Arsenic Trioxide Injection in combination with tretinoin in pediatric patients has not been established.The safety and efficacy of Arsenic Trioxide Injection as single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: to 16 years) were treated with Arsenic Trioxide Injection at the recommended dose of 0.15 mg/kg/day. literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from to 21 years. No differences in efficacy and safety were observed by age.. 8.5 Geriatric Use. Use of Arsenic Trioxide Injection in combination with tretinoin in newly-diagnosed adult patients with low-risk APL is supported by randomized, controlled trial that included 16 patients between the ages of 60 and 70 years. No overall differences in safety or effectiveness were observed between these patients and younger patients. literature review included an additional 77 patients aged 60 to 84 years who were treated with arsenic trioxide in combination with tretinoin as part of induction and consolidation therapy for low- and high-risk APL. These studies showed lower survival rates in older patients. Monitor elderly patients frequently during treatment with Arsenic Trioxide Injection.Use of Arsenic Trioxide Injection as monotherapy in patients with relapsed or refractory APL is supported by the open-label, single-arm trial that included patients aged 65 and older (range: 65 to 73 years). literature review included an additional 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.. 8.6 Renal Impairment. Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min) frequently for toxicity; dose reduction may be warranted.The use of Arsenic Trioxide Injection in patients on dialysis has not been studied.. 8.7 Hepatic Impairment. Since limited data are available across all hepatic impairment groups, caution is advised in the use of Arsenic Trioxide Injection in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Monitor patients with severe hepatic impairment (Child-Pugh Class C) frequently for toxicity.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hepatotoxicity: Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly diagnosed low-risk APL treated with Arsenic Trioxide Injection in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution. (2.3, 5.4)Carcinogenesis: Arsenic trioxide is 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 fetus and use of effective contraception. (5.6, 8.1, 8.3). Hepatotoxicity: Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly diagnosed low-risk APL treated with Arsenic Trioxide Injection in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution. (2.3, 5.4). Carcinogenesis: Arsenic trioxide is 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 fetus and use of effective contraception. (5.6, 8.1, 8.3). 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 Injection. In clinical trials, 16-23% of patients treated with Arsenic Trioxide Injection 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 of induction to as late as the second month induction therapy.When Arsenic Trioxide Injection is used in combination with tretinoin, prophylaxis with prednisone is recommended during the induction cycle [see Dosage and Administration (2.1)].If differentiation syndrome is suspected, temporarily withhold Arsenic Trioxide Injection and immediately initiate dexamethasone 10 mg intravenously every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for minimum of days [see Dosage and Administration (2.3)].. 5.2 Cardiac Conduction Abnormalities. Patients treated with Arsenic Trioxide Injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trials of patients with newly-diagnosed low-risk APL treated with Arsenic Trioxide Injection in combination with tretinoin, 11% experienced QTc (Framingham formula) prolongation 450 msec for men and 460 msec for women throughout the treatment cycles. In the clinical trial of patients with relapsed or refractory APL treated with Arsenic Trioxide Injection monotherapy, 40% had at least one ECG tracing with QTc interval greater than 500 msec. prolonged QTc was observed between and weeks after start of Arsenic Trioxide Injection infusion, and it usually resolved by weeks after Arsenic Trioxide Injection infusion. There are no data on the effect of Arsenic Trioxide Injection 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, 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 Injection 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 Injection, assess the QTc interval by electrocardiogram, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection 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 Injection therapy, maintain potassium concentrations above mEq/L and magnesium concentrations above 1.8 mg/dL. Monitor ECG weekly and more frequently for clinically unstable patients.For patients who develop QTc Framingham greater than 450 msec for men or greater than 460 msec for women, withhold Arsenic Trioxide Injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume Arsenic Trioxide Injection at reduced dose [see Dosage and Administration (2.3)].. 5.3 Encephalopathy. Serious encephalopathies were reported in patients receiving Arsenic Trioxide Injection. 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.. Wernickes EncephalopathyWernickes encephalopathy occurred in patients receiving Arsenic Trioxide Injection. Wernickes encephalopathy is 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 Injection. If Wernickes encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.. 5.4 Hepatotoxicity. In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with Arsenic Trioxide Injection in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of Arsenic Trioxide Injection and/or tretinoin. Long-term liver abnormalities can occur in patients with APL treated with Arsenic Trioxide Injection in combination with tretinoin. In published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at median of years (range to 14 years) after treatment with arsenic trioxide in combination with tretinoin. During treatment with Arsenic Trioxide Injection, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection and/or tretinoin if elevations in AST or alkaline phosphatase occur to greater than times the upper limit of normal and/or elevation in serum total bilirubin occurs to greater than times the upper limit of normal and resume at reduced dose upon resolution [see Dosage and Administration (2.3)].. 5.5 Carcinogenesis. The active ingredient of Arsenic Trioxide Injection, arsenic trioxide, is human carcinogen. Monitor patients for the development of second primary malignancies.. 5.6 Embryo-Fetal Toxicity. Arsenic Trioxide Injection can cause fetal harm when administered to pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day at dose approximately 10 times the recommended human daily dose on mg/m2 basis. related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at dose approximately times the projected human dose on mg/m2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on mg/m2 basis. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].