10 ML arsenic trioxide 1 MG/ML Injection

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/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 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.

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 to 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 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 5 days per week during weeks 1 to 4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin (see Table 1). Omit tretinoin during weeks 5 to 6 of the fourth cycle of consolidation. Table 1: Recommended Dosage of Arsenic Trioxide Injection in Combination with Tretinoin Induction (1 cycle) Arsenic trioxide injection 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 Arsenic trioxide injection 0.15 mg/kg once daily intravenously Days 1 to 5 Days 1 to 5 Days 1 to 5 Days 1 to 5 -- -- -- -- Tretinoin a 22.5 mg/m 2 twice daily orally Days 1 to 7 Days 1 to 7 -- -- Days b 1 to 7 Days b 1 to 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 arsenic trioxide injection 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 arsenic trioxide injection is 0.15 mg/kg/day intravenously daily until bone marrow remission or up to a maximum of 60 days. For the consolidation cycle, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction cycle. 2.3 Monitoring and Dosage Modifications for Adverse Reactions During induction, monitor coagulation studies, blood counts, and chemistries at least 2 to 3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly. Table 2 shows the dosage modifications for adverse reactions due to arsenic trioxide injection when used alone or in combination with tretinoin. Table 2: Dosage Modifications for Adverse Reactions of Arsenic Trioxide Injection Adverse Reaction Dosage Modification Differentiation syndrome, defined by the presence of 2 or more of the following: - Unexplained fever - Dyspnea - Pleural and/or pericardial effusion - Pulmonary infiltrates - Renal failure - Hypotension - Weight gain greater than 5 kg [see Warnings and Precautions (5.1) ] Temporarily withhold arsenic trioxide injection. 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 arsenic trioxide injection 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 arsenic trioxide injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. After the QTc normalizes and electrolyte abnormalities are corrected, resume treatment with arsenic trioxide injection at a 50% reduced dose (0.075 mg/kg/day daily) for one week after resolution. If the 50% reduced dose is tolerated for one week (in the absence of QTc prolongation), increase the dose of arsenic trioxide injection to 0.11 mg/kg/day daily for the next week [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 1 or more of the following: −Total bilirubin (TB) greater than 3 times the upper limit of normal (ULN) −Aspartate aminotransferase (AST) greater than 5 times the ULN −Alkaline phosphatase (AP) greater than 5 times the ULN [see Warnings and Precautions (5.4) ] Withhold arsenic trioxide injection 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 to 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 2 dose levels (see Table 3 below). Moderate (grade 2) nonhematologic reactions [see Adverse Reactions (6) ] Reduce the dose of arsenic trioxide injection 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 arsenic trioxide injection 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 arsenic trioxide injection and tretinoin at 1 dose level lower (see Table 3 below). Table 3: Dose Reduction Levels for Hematologic and Nonhematologic Toxicities *Rounded to the nearest 10 mg increment Dose Level Arsenic Trioxide Injection 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 2.4 Preparation and Administration Reconstitution Dilute 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. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administer arsenic trioxide injection a

WARNINGS AND PRECAUTIONS Hepatotoxicit y : Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly-diagnosed low-risk APL treated with arsenic trioxide in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold arsenic trioxide for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution. ( 2.3 , 5.4 ) Carcinogenesis : Arsenic trioxide is a human carcinogen. Monitor patients for the development of second primary malignancies. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Differentiation Syndrome Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide. In clinical trials, 16 to 23% of patients treated with arsenic trioxide for APL developed differentiation syndrome. Signs and symptoms include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction. Differentiation syndrome has been observed with and without concomitant leukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. When arsenic trioxide 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 and immediately initiate dexamethasone 10 mg intravenously every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for a minimum of 3 days [see Dosage and Administration (2.3) ] . 5.2 Cardiac Conduction Abnormalities Patients treated with arsenic trioxide 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 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 monotherapy, 40% had at least one ECG tracing with a QTc interval greater than 500 msec. A prolonged QTc was observed between 1 and 5 weeks after start of arsenic trioxide infusion, and it usually resolved by 8 weeks after arsenic trioxide infusion. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion of the drug. The risk of torsade de pointes is related to the extent of QTc prolongation, concomitant administration of QTc prolonging drugs, a history of torsade de pointes, pre-existing QTc interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. The risk may be increased when arsenic trioxide is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) [see Drug Interactions (7) ] . Prior to initiating therapy with arsenic trioxide, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide to patients with a ventricular arrhythmia or prolonged QTc. If possible, discontinue drugs that are known to prolong the QTc interval. If it is not possible to discontinue the interacting drug, perform cardiac monitoring frequently [see Drug Interactions (7) ] . During arsenic trioxide therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Monitor ECG weekly and more frequently for clinically unstable patients. For patients who develop a QTc Framingham greater than 450 msec for men or greater than 460 msec for women, withhold arsenic trioxide and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume arsenic trioxide at a reduced dose [see Dosage and Administration (2.3) ] . 5.3 Encephalopathy Serious encephalopathies were reported in patients receiving arsenic trioxide. Monitor patients for neurological symptoms, such as confusion, decreased level of consciousness, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction. Advise patients and caregivers of the need for close observation. Wernicke's Encephalopathy Wernicke's encephalopathy occurred in patients receiving arsenic trioxide. Wernicke’s encephalopathy is a neurologic emergency that can be prevented and treated with thiamine. Consider testing thiamine levels in patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide). Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving arsenic trioxide. If Wernicke's encephalopathy is suspected, immediately interrupt arsenic trioxide and initiate parenteral thiamine. 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 in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of arsenic trioxide and/or tretinoin. Long-term liver abnormalities can occur in patients with APL treated with arsenic trioxide in combination with tretinoin. In a published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at a median of 7 years (range 0 to 14 years) after treatment with arsenic trioxide in combination with tretinoin. During treatment with arsenic trioxide, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold arsenic trioxide and/or tretinoin if elevations in AST or alkaline phosphatase occur to greater than 5 times the upper limit of normal and/or elevation in serum total bilirubin occurs to greater than 3 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 a human carcinogen. Monitor patients for the development of second primary malignancies. 5.6 Embryo-Fetal Toxicity Arsenic trioxide can cause fetal harm when administered to a pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/m² basis. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

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

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.