Arsenic Trioxide

1 INDICATIONS AND USAGE TRISENOX 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/RAR-alpha 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 TRISENOX 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 TRISENOX 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.

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 5 days per week during weeks 1-4 of each 8-week cycle for a total of 4 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 a period of up to 5 weeks. ( 2.2 ) 2.1 Recommended Dosage for Newly-Diagnosed Low-Risk Acute Promyelocytic Leukemia (APL) A treatment course for patients with newly-diagnosed low-risk APL consists of 1 induction cycle and 4 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 5 days per week during weeks 1-4 of each 8-week cycle for a total of 4 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 Tretinoin Induction (1 cycle) TRISENOX 0.15 mg/kg once daily intravenously until marrow remission but not to exceed 60 days Tretinoin a 22.5 mg/m 2 twice daily orally until marrow remission but not to exceed 60 days Consolidation (4 cycles) Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 TRISENOX 0.15 mg/kg once daily intravenously Days 1-5 Days 1-5 Days 1-5 Days 1-5 -- -- -- -- Tretinoin a 22.5 mg/m 2 twice daily orally Days 1-7 Days 1-7 -- -- Days b 1-7 Days b 1-7 -- -- a Rounded to the nearest 10 mg increment b Omitted during the 4th cycle of consolidation Differentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day 1 until the end of induction cycle with TRISENOX and tretinoin is recommended. 2.2 Recommended Dosage for Relapsed or Refractory APL A treatment course for patients with relapsed or refractory APL consists of 1 induction cycle and 1 consolidation cycle [see Clinical Studies ( 14.2 )] . For the induction cycle, the recommended dosage of TRISENOX is 0.15 mg/kg/day intravenously daily until bone marrow remission or up to a maximum of 60 days. For the consolidation cycle, the recommended dosage of TRISENOX is 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction cycle. 2.3 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 2 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 TRISENOX Adverse Reaction Dosage Modification Differentiation syndrome, defined by the presence of 2 or more of the following: Unexplained fever Dyspnea Pleural and/or pericardial effusion Pulmonary infiltrates Renal failure Hypotension Weight gain greater than 5 kg [see Warnings and Precautions ( 5.1 )] Temporarily withhold TRISENOX. Consider holding tretinoin if symptoms are severe. Administer dexamethasone 10 mg intravenously every 12 hours until the resolution of signs and symptoms for a minimum of 3 days. Resume treatment when the clinical condition improves and reduce the dose of the withheld drug(s) by 50%. Increase the dose of the withheld drug(s) to the recommended dosage after one week in the absence of recurrence of symptoms of differentiation syndrome. If symptoms re-appear, decrease 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 a 50% reduced dose (0.075 mg/kg/day daily) for one week after resolution. If the 50% reduced dose is tolerated for one week (in the absence of QTc prolongation), increase the dose of 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 1 or more of the following: Total bilirubin (TB) greater than 3 times the upper limit of normal (ULN) Aspartate aminotransferase (AST) greater than 5 times the ULN Alkaline phosphatase (AP) greater than 5 times the ULN [see Warnings and Precautions ( 5.4 )] Withhold TRISENOX and/or tretinoin. Resume treatment at a 50% reduced dose of the withheld drug(s) when TB is less than 1.5 times the ULN and AP/AST are less than 3 times the ULN. Increase the dose of the withheld drug(s) back to the recommended dosage after one week on the reduced dose in the absence of worsening of hepatotoxicity. Discontinue the withheld drug(s) permanently if hepatotoxicity recurs. Other severe or life-threatening (grade 3-4) 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 2 dose levels (see Table 3 below). Moderate (grade 2) nonhematologic reactions [see Adverse Reactions ( 6 )] Reduce the dose of TRISENOX and/or tretinoin by 1 dose level (see Table 3 below). Leukocytosis (WBC count greater than 10 Gi/L) [see Adverse Reactions ( 6.1 )] Administer hydroxyurea. Hydroxyurea may be discontinued when the WBC declines below 10 Gi/L. Myelosuppression, defined by 1 or more of the following: absolute neutrophil count less than 1 Gi/L platelets less than 50 Gi/L lasting more than 5 weeks [see Adverse Reactions ( 6 )] Consider reducing the dose of TRISENOX and tretinoin by 1 dose level (see Table 3 below). If myelosuppression lasts ≥ 50 days or occurs on 2 consecutive cycles, assess a marrow aspirate for remission status. In the case of molecular remission, resume TRISENOX and tretinoin at 1 dose level lower (see Table 3 below). Table 3: Dose Reduction Levels for Hematologic and Nonhematologic Toxicities Dose Level TRISENOX mg/kg intravenously once daily Tretinoin* mg/m 2 orally twice daily Starting level 0.15 22.5 -1 0.11 18.75 -2 0.10 12.5 -3 0.075 10 *Rounded to the nearest 10 mg increment 2.4 Preparation and Administration Reconstitution Dilute 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. Administration Parenteral 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 2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required. The 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 a hazardous drug. Follow applicable special handling and disposal procedures. 1

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] Cardiac Conduction Abnormalities [see Warnings and Precautions ( 5.2 )] Encephalopathy [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Carcinogenesis [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (> 30%) are nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact 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 a 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 APL The safety of TRISENOX in combination with tretinoin was evaluated in Study APL0406, a 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 (1%) patient on the TRISENOX/tretinoin arm and 8 (6%) patients on the chemotherapy/tretinoin arm. TRISENOX/tretinoin was discontinued due to toxicity in 1 patient during induction and in 4 patients during the first three consolidation courses, whereas chemotherapy/tretinoin was discontinued due to toxicity in 4 patients during induction and in 6 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 APL0406 Induction First Consolidation Second Consolidation Third Consolidation Adverse Reaction n (%) n (%) n (%) n (%) Thrombocytopenia > 15 days (Grade 3-4) TRISENOX/tretinoin 74 (58%) 6 (5%) 6 (5%) 8 (7%) Chemotherapy/tretinoin 120 (88%) 17 (14%) 77 (63%) 26 (22%) Neutropenia >15 days (Grade 3-4) TRISENOX/tretinoin 61 (48%) 8 (7%) 7 (6%) 5 (4%) Chemotherapy/tretinoin 109 (80%) 40 (32%) 90 (73%) 28 (24%) Hepatic toxicity (Grade 3-4) TRISENOX/tretinoin 51 (40%) 5 (4%) 1 (1%) 0 (0%) Chemotherapy/tretinoin 4 (3%) 1 (1%) 0 (0%) 0 (0%) Infection and fever of unknown origin TRISENOX/tretinoin 30 (23%) 10 (8%) 4 (3%) 2 (2%) Chemotherapy/tretinoin 75 (55%) 8 (6%) 46 (38%) 2 (2%) Hypertriglyceridemia TRISENOX/tretinoin 29 (22%) 22 (18%) 17 (14%) 16 (14%) Chemotherapy/tretinoin 29 (22%) 19 (15%) 10 (8%) 13 (11%) Hypercholesterolemia TRISENOX/tretinoin 14 (10%) 19 (16%) 19 (16%) 16 (14%) Chemotherapy/tretinoin 12 (9%) 12 (10%) 12 (10%) 11 (9%) QT prolongation TRISENOX/tretinoin 11 (9%) 3 (2%) 3 (2%) 2 (2%) Chemotherapy/tretinoin 1 (1%) 0 (0%) 0 (0%) 0 (0%) Gastrointestinal toxicity (Grade 3-4) TRISENOX/tretinoin 3 (2%) 0 (0%) 0 (0%) 0 (0%) Chemotherapy/tretinoin 25 (18%) 1 (1%) 6 (5%) 0 (0%) Neurotoxicity* TRISENOX/tretinoin 1 (1%) 5 (4%) 6 (5%) 7 (6%) Chemotherapy/tretinoin 0 (0%) 0 (0%) 0 (0%) 0 (0%) Cardiac function (Grade 3-4) TRISENOX/tretinoin 0 (0%) 0 (0%) 0 (0%) 0 (0%) Chemotherapy/tretinoin 5 (4%) 0 (0%) 0 (0%) 0 (0%) *Mostly cases of reversible peripheral neuropathy Relapsed or Refractory APL Safety 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, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2). The most common adverse reactions (> 30%) were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus. Table 5 describes the adverse reactions in patients aged 5 to 73 years with APL who received 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 PLRXAS01 Body System Adverse reaction Any Grade Adverse Reactions Grade ≥3 Adverse Reactions n % n % Gastrointestinal disorders Nausea 30 75 Abdominal pain (lower & upper) 23 58 4 10 Vomiting 23 58 Diarrhea 21 53 Sore throat 14 35 Constipation 11 28 1 3 Anorexia 9 23 Appetite decreased 6 15 Loose stools 4 10 Dyspepsia 4 10 Oral blistering 3 8 Fecal incontinence 3 8 Gastrointestinal hemorrhage 3 8 Dry mouth 3 8 Abdominal tenderness 3 8 Diarrhea hemorrhagic 3 8 Abdominal distension 3 8 Respiratory Cough 26 65 Dyspnea 21 53 4 10 Epistaxis 10 25 Hypoxia 9 23 4 10 Pleural effusion 8 20 1 3 Post nasal drip 5 13 Wheezing 5 13 Decreased breath sounds 4 10 Crepitations 4 10 Rales 4 10 Hemoptysis 3 8 Tachypnea 3 8 Rhonchi 3 8 General disorders and administration site conditions Fatigue 25 63 2 5 Pyrexia (fever) 25 63 2 5 Edema - non-specific 16 40 Rigors 15 38 Chest pain 10 25 2 5 Injection site pain 8 20 Pain - non-specific 6 15 1 3 Injection site erythema 5 13 Weight gain 5 13 Injection site edema 4 10 Weakness 4 10 2 5 Hemorrhage 3 8 Weight loss 3 8 Drug hypersensitivity 2 5 1 3 Nervous system disorders Headache 24 60 1 3 Insomnia 17 43 1 3 Paresthesia 13 33 2 5 Dizziness (excluding vertigo) 9 23 Tremor 5 13 Convulsion 3 8 2 5 Somnolence 3 8 Coma 2 5 2 5 Cardiac disorders Tachycardia 22 55 ECG QT corrected interval prolonged > 500 msec 16 40 Palpitations 4 10 ECG abnormal other than QT interval prolongation 3 8 Metabolism and nutrition disorders Hypokalemia 20 50 5 13 Hypomagnesemia 18 45 5 13 Hyperglycemia 18 45 5 13 ALT increased 8 20 2 5 Hyperkalemia 7 18 2 5 AST increased 5 13 1 3 Hypocalcemia 4 10 Hypoglycemia 3 8 Acidosis 2 5 Hematologic disorders Leukocytosis 20 50 1 3 Anemia 8 20 2 5 Thrombocytopenia 7 18 5 13 Febrile neutropenia 5 13 3 8 Neutropenia 4 10 4 10 Disseminated intravascular coagulation 3 8 3 8 Lymphadenopathy 3 8 Skin and subcutaneous tissue disorders Dermatitis 17 43 Pruritus 13 33 1 3 Ecchymosis 8 20 Dry skin 6 15 Erythema - non-specific 5 13 Increased sweating 5 13 Facial edema 3 8 Night sweats 3 8 Petechiae 3 8 Hyperpigmentation 3 8 Non-specific skin lesions 3 8 Urticaria 3 8 Local exfoliation 2 5 Eyelid edema 2 5 Musculoskeletal, connective tissue, and bone disorders Arthralgia 13 33 3 8 Myalgia 10 25 2 5 Bone pain 9 23 4 10 Back pain 7 18 1 3 Neck pain 5 13 Pain in limb 5 13 2 5 Psychiatric disorders Anxiety 12 30 Depression 8 20 Agitation 2 5 Confusion 2 5 Vascular disorders Hypotension 10 25 2 5 Flushing 4 10 Hypertension 4 10 Pallor 4 10 Infections and infestations Sinusitis 8 20 Herpes simplex 5 13 Upper respiratory tract infection 5 13 1 3 Bacterial infection - non-specific 3 8 1 3 Herpes zoster 3 8 Nasopharyngitis 2 5 Oral candidiasis 2 5 Sepsis 2 5 2 5 Reproductive system disorders Vaginal hemorrhage 5 13 Intermenstrual bleeding 3 8 Ocular disorders Eye irritation 4 10 Blurred vision 4 10 Dry eye 3 8 Painful red eye 2 5 Renal and urinary disorders Renal failure 3 8 1 3 Renal impairment 3 8 Oliguria 2 5 Incontinence 2 5 Ear disorders Earache 3 8 Tinnitus 2 5 Other Clinically Relevant Adverse Reactions Leukocytosis TRISENOX can induce proliferation of leukemic promyelocytes resulting in a 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, a 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 a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a 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 failure Ear and labyrinth disorders: Deafness Hematologic disorders: Pancytopenia, bone marrow necrosis Infections: Herpes zoster Investigations: Gamma-glutamyltransferase increased Musculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysis Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernicke's encephalopathy, posterior reversible encephalopathy syndrome Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis

12.3 Pharmacokinetics The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As III ). As III is the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMA V ), and dimethylarsinic acid (DMA V ) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (As V ) a product of As III oxidation. The pharmacokinetics of arsenical species ([As III ], [As V ], [MMA V ], [DMA V ]) were determined in 6 APL patients following once-daily doses of 0.15 mg/kg for 5 days per week. Over the total single-dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. Peak plasma concentrations of arsenious acid (As III ), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of As III declined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to As III (mean AUC 0-24h ) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2-fold accumulation. The primary pentavalent metabolites, MMA V and DMA V , are slow to appear in plasma (approximately 10 to 24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does As III . The mean estimated terminal elimination half-lives of the metabolites MMA V and DMA V are 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single-dose administration. As V is present in plasma only at relatively low levels. Distribution The volume of distribution (V ss ) for As III is large (mean 562 L, N=10) indicating that As III is widely distributed throughout body tissues. V ss is also dependent on body weight and increases as body weight increases. Elimination Metabolism Much of the As III is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMA V ) and dimethylarsinic acid (DMA V ) by methyltransferases primarily in the liver. The metabolism of arsenic trioxide also involves oxidation of As III to As V , which may occur in numerous tissues via enzymatic or nonenzymatic processes. As V is present in plasma only at relatively low levels following administration of arsenic trioxide. Excretion Approximately 15% of the administered TRISENOX dose is excreted in the urine as unchanged As III . The methylated metabolites of As III (MMA V , DMA V ) are primarily excreted in the urine. The total clearance of As III is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on body weight or dose administered over the range of 7 to 32 mg. Specific Populations Patients with Renal Impairment The effect of renal impairment on the pharmacokinetics of As III , As V , and the pentavalent metabolites MMA V and DMA V was evaluated in 20 patients with advanced malignancies. Patients were classified as having 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 a 2-hour infusion, the mean AUC 0-INF for As III was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC 0-INF for As III was approximately 48% higher than that in the normal group. Systemic exposure to MMA V and DMA V tended to be larger in patients with renal impairment; however, the clinical consequences of this increased exposure are not known. As V 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 Impairment The effect of pharmacokinetics of As III , As V , and the pentavalent metabolites MMA V and DMA V 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 As III , As V , MMA V or DMA V 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 AUC 0‑24h and C max values 40% and 70% higher, respectively, than those patients with normal hepatic function. The mean dose-normalized trough plasma levels for both MMA V and DMA V 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 Patients Following 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 As III (mean AUC 0-24h ) was 317 ng·hr/mL on Day 1 of Cycle 1 [see Use in Specific Populations ( 8.4 )] . Drug Interaction Studies No 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.