CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of TRISENOX 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 TRISENOX (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 TRISENOX infusion, and then returned towards baseline by the end of weeks after TRISENOX 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 to 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. EliminationMetabolism Much 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 TRISENOX 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 to 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 [CLcr] 80 mL/min, n=6), mild renal impairment (CLcr 50 to 80 mL/min, n=5), moderate renal impairment (CLcr 30 to 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 to 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 TRISENOX 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. TRISENOX 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 TRISENOX/tretinoin for induction and consolidation or chemotherapy/tretinoin for induction, consolidation, and maintenance. Patients in the TRISENOX/tretinoin group received induction treatment with TRISENOX 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 TRISENOX 0.15 mg/kg intravenously once daily for days every week during weeks to 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 to and to of the 8-week cycle. Tretinoin was omitted during weeks to 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 TRISENOX/tretinoin arm and 47 years in the chemotherapy/tretinoin arm, and 52% and 46% were male in the TRISENOX/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 TRISENOX/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 TRISENOX/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). The number of patients in the plot is based on the mITT population. Figure 1. 14.2 Relapsed or Refractory APL. TRISENOX 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 TRISENOX 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 TRISENOX >= 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 TRISENOX, at the same dose, for 25 additional days over period up to weeks. In follow-up treatment, 18 patients received further TRISENOX 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.

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: Administer 0.15 mg/kg/day intravenously daily for days per week during weeks 1-4 of each 8-week cycle for total of cycles in combination with tretinoin. (2.1)Relapsed or refractory APL:Induction: Administer 0.15 mg/kg/day intravenously daily until bone marrow remission. Do not exceed 60 days. (2.2)Consolidation: Administer 0.15 mg/kg/day intravenously daily for 25 doses over period of 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: Administer 0.15 mg/kg/day intravenously daily for days per week during weeks 1-4 of each 8-week cycle for total of cycles in combination with tretinoin. (2.1). Induction: Administer 0.15 mg/kg/day intravenously daily until bone marrow remission. Do not exceed 60 days. (2.2). Consolidation: Administer 0.15 mg/kg/day intravenously daily for 25 doses over period of 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 TRISENOX 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 TRISENOX 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 TRISENOX in Combination with TretinoinInduction (1 cycle)TRISENOX0.15 mg/kg oncedaily intravenouslyuntil marrow remission but not to exceed 60 daysTretinoina 22.5 mg/m2 twice daily orallyuntil marrow remission but not to exceed 60 daysConsolidation (4 cycles)Week 1Week 2Week 3Week 4Week 5Week 6Week 7Week 8TRISENOX 0.15 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----aRounded to the nearest 10 mg incrementbOmitted during the 4th cycle of consolidationDifferentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day until the end of induction cycle with TRISENOX and tretinoin is recommended.. For the induction cycle, the recommended dosage of TRISENOX 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 TRISENOX 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 Dosagefor Relapsedor 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 TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX when used alone or in combination with tretinoin.Table 2: Dosage Modifications for Adverse Reactions of TRISENOXAdverse ReactionDosage ModificationDifferentiation syndrome, defined by the presence of or more of the following: Unexplained feverDyspneaPleural and/or pericardial effusionPulmonary infiltratesRenal failureHypotension Weight gain greater than kg[see Warnings and Precautions (5.1)]Temporarily withhold TRISENOX. 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 TRISENOX and/or tretinoin to the previous dose.QTc (Framingham formula) Prolongation greater than 450 msec for men or greater than 460 msec for women [see Warnings and Precautions (5.2)] Withhold TRISENOX and any medication known to prolong the QTc interval.Correct electrolyte abnormalities.After the QTc normalizes and electrolyte abnormalities are corrected, resume treatment with TRISENOX 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 TRISENOX to 0.11 mg/kg/day daily for the next week [see Dosage and Administration (2.1)]. The dose of TRISENOX 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 TRISENOX 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 TRISENOX and tretinoin.When the adverse reaction resolves to no more than mild (grade 1), resume TRISENOX and tretinoin reduced by dose levels (see Table below).Moderate (grade 2) nonhematologic reactions [see Adverse Reactions (6)]Reduce the dose of TRISENOX 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 TRISENOX 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 TRISENOX and tretinoin at dose level lower (see Table below).Table 3: Dose Reduction Levels for Hematologic and Nonhematologic ToxicitiesDose LevelTRISENOXmg/kg intravenouslyonce dailyTretinoinmg/m2 orallytwice dailyStarting level0.1522.5-10.1118.75-20.1012.5-30.07510Rounded to the nearest 10 mg increment. Unexplained fever. Dyspnea. Pleural and/or pericardial effusion. Pulmonary infiltrates. Renal failure. Hypotension. Weight gain greater than kg. Temporarily withhold TRISENOX. 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 TRISENOX and/or tretinoin to the previous dose.. Withhold TRISENOX and any medication known to prolong the QTc interval.. Correct electrolyte abnormalities.. After the QTc normalizes and electrolyte abnormalities are corrected, resume treatment with TRISENOX 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 TRISENOX to 0.11 mg/kg/day daily for the next week [see Dosage and Administration (2.1)]. The dose of TRISENOX 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 TRISENOX 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 TRISENOX and tretinoin.. When the adverse reaction resolves to no more than mild (grade 1), resume TRISENOX and tretinoin reduced by dose levels (see Table below).. Reduce the dose of TRISENOX 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 TRISENOX 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 TRISENOX and tretinoin at dose level lower (see Table below).. 2.4 Preparation and Administration. ReconstitutionDilute TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly. Do not mix TRISENOX with other medications.Safe Handling Procedures TRISENOX is hazardous drug. Follow applicable special handling and disposal procedures.1.

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 to 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. EliminationMetabolism Much 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 TRISENOX 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 to 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 [CLcr] 80 mL/min, n=6), mild renal impairment (CLcr 50 to 80 mL/min, n=5), moderate renal impairment (CLcr 30 to 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 to 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 TRISENOX 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Differentiation Syndrome Advise patients that symptoms of APL differentiation syndrome include fever, sudden weight gain, dizziness/lightheadedness, labored breathing, and accumulation of fluid in the lungs, heart, and chest. This syndrome is managed by immediate treatment with high-dose corticosteroids. Advise patients to immediately report any of these symptoms [see Warnings and Precautions (5.1)]. Cardiac Conduction Abnormalities Advise patients that TRISENOX 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 TRISENOX 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 Toxicity Advise 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 TRISENOX 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 TRISENOX for months after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with TRISENOX and for weeks after the last dose [see Use in Specific Populations (8.2)].InfertilityAdvise males of reproductive potential that TRISENOX may impair fertility [see Use in Specific Population (8.3)].Other Adverse Reactions Advise patients of the expected adverse reactions of TRISENOX. 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)].Distributed by: Teva Pharmaceuticals USA, Inc.Parsippany, NJ 07054(C)2020 Cephalon, Inc., wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd., or its affiliates. All rights reserved.TRI-014.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, TRISENOX 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 TRISENOX 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. DataHuman 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 Data Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were observed in rats administered 10 mg/kg of arsenic trioxide on gestation day (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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise 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 TRISENOX; dose reduction may be warranted. (8.6)Hepatic Impairment: Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with TRISENOX. (8.7). Lactation: Advise 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 TRISENOX; dose reduction may be warranted. (8.6). Hepatic Impairment: Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with TRISENOX. (8.7). 8.1 Pregnancy. Risk SummaryBased on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, TRISENOX 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 TRISENOX 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. DataHuman 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 Data Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were observed in rats administered 10 mg/kg of arsenic trioxide on gestation day (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 TRISENOX and for weeks after the final dose.. 8.3 Females and Males of Reproductive Potential. TRISENOX 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 TRISENOX. ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with TRISENOX and for months after the final dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with TRISENOX and for months after the final dose.InfertilityMalesBased on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, TRISENOX may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and efficacy of TRISENOX in combination with tretinoin in pediatric patients has not been established. The safety and efficacy of TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX. Use of TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold TRISENOX 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 TRISENOX in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold TRISENOX 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 TRISENOX. In clinical trials, 16-23% of patients treated with TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX infusion, and it usually resolved by weeks after TRISENOX infusion. There are no data on the effect of TRISENOX 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 TRISENOX 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 TRISENOX, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX 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 TRISENOX 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 TRISENOX and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume TRISENOX at reduced dose [see Dosage and Administration (2.3)]. 5.3 Encephalopathy. Serious encephalopathies were reported in patients receiving TRISENOX. 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 TRISENOX. 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 TRISENOX. If Wernickes encephalopathy is suspected, immediately interrupt TRISENOX 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 TRISENOX in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of TRISENOX and/or tretinoin. Long-term liver abnormalities can occur in patients with APL treated with TRISENOX 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 TRISENOX, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold TRISENOX 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 TRISENOX, arsenic trioxide, is human carcinogen. Monitor patients for the development of second primary malignancies. 5.6 Embryo-Fetal Toxicity. TRISENOX 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 TRISENOX and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TRISENOX and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].

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)] Differentiation Syndrome [see Warnings and Precautions (5.1)] Cardiac Conduction Abnormalities [see Warnings and Precautions (5.2)] Encephalopathy [see Warnings and Precautions (5.3)] Hepatotoxicity [see Warnings and Precautions (5.4)] Carcinogenesis [see Warnings and Precautions (5.5)] The most common adverse reactions (> 30%) are nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 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 TRISENOX in combination with tretinoin was evaluated in Study APL0406, randomized trial comparing TRISENOX plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL [see Clinical Studies (14.1)]. In the TRISENOX/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 TRISENOX/tretinoin arm and 24% on the chemotherapy/tretinoin arm. The serious adverse reactions reported in >= 2% of patients who received TRISENOX/tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections. Fatal adverse reactions were reported in (1%) patient on the TRISENOX/tretinoin arm and (6%) patients on the chemotherapy/tretinoin arm. TRISENOX/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 Trisenox in Combination with Tretinoin in Patients with Newly-Diagnosed APL in Study APL0406InductionFirst ConsolidationSecond ConsolidationThird ConsolidationAdverse Reactionn (%)n (%)n (%)n (%)Thrombocytopenia 15 days (Grade 3-4)TRISENOX/tretinoin74 (58%)6 (5%)6 (5%)8 (7%)Chemotherapy/tretinoin120 (88%)17 (14%)77 (63%)26 (22%)Neutropenia >15 days (Grade 3-4)TRISENOX/tretinoin61 (48%)8 (7%)7 (6%)5 (4%)Chemotherapy/tretinoin109 (80%)40 (32%)90 (73%)28 (24%)Hepatic toxicity (Grade 3-4)TRISENOX/tretinoin51 (40%)5 (4%)1 (1%)0 (0%)Chemotherapy/tretinoin4 (3%)1 (1%)0 (0%)0 (0%)Infection and fever of unknown originTRISENOX/tretinoin30 (23%)10 (8%)4 (3%)2 (2%)Chemotherapy/tretinoin75 (55%)8 (6%)46 (38%)2 (2%)HypertriglyceridemiaTRISENOX/tretinoin29 (22%)22 (18%)17 (14%)16 (14%)Chemotherapy/tretinoin29 (22%)19 (15%)10 (8%)13 (11%)HypercholesterolemiaTRISENOX/tretinoin14 (10%)19 (16%)19 (16%)16 (14%)Chemotherapy/tretinoin12 (9%)12 (10%)12 (10%)11 (9%)QT prolongationTRISENOX/tretinoin11 (9%)3 (2%)3 (2%)2 (2%)Chemotherapy/tretinoin1 (1%)0 (0%)0 (0%)0 (0%)Gastrointestinal toxicity (Grade 3-4)TRISENOX/tretinoin3 (2%)0 (0%)0 (0%)0 (0%)Chemotherapy/tretinoin25 (18%)1 (1%)6 (5%)0 (0%)NeurotoxicityTRISENOX/tretinoin1 (1%)5 (4%)6 (5%)7 (6%)Chemotherapy/tretinoin0 (0%)0 (0%)0 (0%)0 (0%)Cardiac function (Grade 3-4)TRISENOX/tretinoin0 (0%)0 (0%)0 (0%)0 (0%)Chemotherapy/tretinoin5 (4%)0 (0%)0 (0%)0 (0%)Mostly cases of reversible peripheral neuropathyRelapsed or Refractory APLSafety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of TRISENOX. 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 TRISENOX at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received TRISENOX.Table 5: Adverse Reactions (>= 5%) in Patients with Relapsed or Refractory APL Who Received TRISENOX in Study PLRXAS01Body System Adverse reactionAny Grade Adverse ReactionsGrade >=3 Adverse Reactionsn%n%Gastrointestinal disordersNausea3075Abdominal pain (lower upper)2358410Vomiting2358Diarrhea2153Sore throat1435Constipation112813Anorexia923Appetite decreased615Loose stools410Dyspepsia410Oral blistering38Fecal incontinence38Gastrointestinal hemorrhage38Dry mouth38Abdominal tenderness38Diarrhea hemorrhagic38Abdominal distension38RespiratoryCough2665Dyspnea2153410Epistaxis1025Hypoxia923410Pleural effusion82013Post nasal drip513Wheezing513Decreased breath sounds410Crepitations410Rales410Hemoptysis38Tachypnea38Rhonchi38General disorders and administration site conditionsFatigue256325Pyrexia (fever)256325Edema non-specific1640Rigors1538Chest pain102525Injection site pain820Pain non-specific61513Injection site erythema513Weight gain513Injection site edema410Weakness41025Hemorrhage38Weight loss38Drug hypersensitivity2513Nervous system disordersHeadache246013Insomnia174313Paresthesia133325Dizziness (excluding vertigo)923Tremor 513Convulsion3825Somnolence38Coma2525Cardiac disordersTachycardia2255ECG QT corrected interval prolonged 500 msec1640Palpitations410ECG abnormal other than QT interval prolongation38Metabolism and nutrition disordersHypokalemia2050513Hypomagnesemia1845513Hyperglycemia1845513ALT increased82025Hyperkalemia71825AST increased51313Hypocalcemia410Hypoglycemia 38Acidosis25Hematologic disordersLeukocytosis205013Anemia82025Thrombocytopenia718513Febrile neutropenia51338Neutropenia410410Disseminated intravascular coagulation3838Lymphadenopathy38Skin and subcutaneous tissue disordersDermatitis1743Pruritus133313Ecchymosis820Dry skin615Erythema non-specific513Increased sweating513Facial edema38Night sweats38Petechiae38Hyperpigmentation38Non-specific skin lesions38Urticaria38Local exfoliation25Eyelid edema25Musculoskeletal, connective tissue, and bone disordersArthralgia133338Myalgia102525Bone pain923410Back pain71813Neck pain513Pain in limb51325Psychiatric disordersAnxiety1230Depression820Agitation25Confusion25Vascular disordersHypotension102525Flushing410Hypertension410Pallor410Infections and infestationsSinusitis820Herpes simplex513Upper respiratory tract infection51313Bacterial infection non-specific3813Herpes zoster38Nasopharyngitis25Oral candidiasis25Sepsis2525Reproductive system disordersVaginal hemorrhage513Intermenstrual bleeding38Ocular disordersEye irritation410Blurred vision410Dry eye38Painful red eye25Renal and urinary disordersRenal failure3813Renal impairment38Oliguria25Incontinence25Ear disordersEarache38Tinnitus25Other Clinically Relevant Adverse ReactionsLeukocytosisTRISENOX 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 TRISENOX/tretinoin for newly-diagnosed low-risk APL and in 50% of patients receiving TRISENOX 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 TRISENOX. 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 WERNICKESDifferentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with TRISENOX have experienced differentiation syndrome, which may be life-threatening or fatal. Signs and symptoms may include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy, and multi-organ dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold TRISENOX [see Dosage and Administration (2.3), Warnings and Precautions (5.1)]. Cardiac Conduction Abnormalities: TRISENOX can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering TRISENOX, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTc interval. Withhold TRISENOX 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 TRISENOX. Wernickes is 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 TRISENOX. If Wernickes encephalopathy is suspected, immediately interrupt TRISENOX 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 TRISENOX have experienced symptoms of differentiation syndrome, which may be life-threatening or fatal. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold TRISENOX. (2.3, 5.1)TRISENOX can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering TRISENOX, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTc interval. ithhold TRISENOX until resolution and resume at reduced dose for QTc prolongation. (2.3, 5.2)Serious encephalopathy, including Wernickes, has occurred with TRISENOX. If Wernickes encephalopathy is suspected, immediately interrupt TRISENOX and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. (5.3). Patients with acute promyelocytic leukemia (APL) treated with TRISENOX have experienced symptoms of differentiation syndrome, which may be life-threatening or fatal. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold TRISENOX. (2.3, 5.1). TRISENOX can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering TRISENOX, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTc interval. ithhold TRISENOX until resolution and resume at reduced dose for QTc prolongation. (2.3, 5.2). Serious encephalopathy, including Wernickes, has occurred with TRISENOX. If Wernickes encephalopathy is suspected, immediately interrupt TRISENOX and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. (5.3).