ARSENIC TRIOXIDE

1 INDICATIONS AND USAGE Arsenic trioxide injection is an arsenical 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. ( 1.2 ) 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.

2 DOSAGE AND ADMINISTRATION 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 ) 2.2 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 2-3 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. 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. ● 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 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. ● 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. ● 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 arsenic trioxide injection. ● When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide injection reduced by 2 dose …

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold arsenic trioxide injection for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution. ( 2.3, 5.4 ) Carcinogenesis: Arsenic trioxide is 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 injection. In clinical trials, 16-23% of patients treated with arsenic trioxide injection for APL developed differentiation syndrome. Signs and symptoms include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction. Differentiation syndrome has been observed with and without concomitant leukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. If differentiation syndrome is suspected, temporarily withhold arsenic trioxide injection and immediately initiate dexamethasone 10 mg intravenously every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for a minimum of 3 days [see Dosage and Administration (2.3) ]. 5.2 Cardiac Conduction Abnormalities Patients treated with arsenic trioxide injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trials of patients with relapsed or refractory APL treated with arsenic trioxide injection 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 injection infusion, and it usually resolved by 8 weeks after arsenic trioxide injection infusion. There are no data on the effect of arsenic trioxide injection on the QTc interval during the infusion of the drug. The risk of torsade de pointes is related to the extent of QTc prolongation, concomitant administration of QTc prolonging drugs, 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 injection is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) [see Drug Interactions (7) ] . Prior to initiating therapy with arsenic trioxide injection, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide injection 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 injection 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 injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume arsenic trioxide injection at a reduced dose [see Dosage and Administration (2.3) ]. 5.3 Enc…

4 CONTRAINDICATIONS Arsenic trioxide injection is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic. ( 4 )

7 DRUG INTERACTIONS Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and arsenic trioxide injection may increase the risk of serious QT/QTc interval prolongation [see Warnings and Precautions (5.1) ] . Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while the patient is using arsenic trioxide injection. Monitor ECGs more frequently in patients when it is not feasible to avoid concomitant use. Drugs That Can Lead to Electrolyte Abnormalities Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation [see Warnings and Precautions (5.1) ] . Avoid concomitant use of drugs that can lead to electrolyte abnormalities. Monitor electrolytes more frequently in patients who must receive concomitant use of these drugs and arsenic trioxide injection. Drugs That Can Lead to Hepatotoxicity Concomitant use of these drugs and arsenic trioxide injection may increase the risk of serious hepatotoxicity [see Warnings and Precautions (5.4) ] . Discontinue or replace with an alternative drug that does not cause hepatotoxicity while the patient is using arsenic trioxide injection. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.

8.1 Pregnancy Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1 )] and findings in animal studies, arsenic trioxide injection can cause fetal harm when administered to 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/m basis (see Data) . A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 basis. There are no studies with the use of arsenic trioxide injection in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data One patient was reported to deliver a live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. A second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have a normal pregnancy outcome. A third patient was a pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had a normal pregnancy outcome after treatment and monitoring. A fourth patient who became pregnant while receiving arsenic trioxide had a miscarriage. Animal 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 9 (approximately 10 times the recommended human daily dose on a mg/m 2 basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite (approximately 5 times the projected human dose on a mg/m 2 basis), on gestation days 6, 7, 8, or 9. Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m 2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.

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 Ingenus Pharmaceuticals, LLC at 1-877-748-1970 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. Relapsed or Refractory APL Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of arsenic trioxide injection. Forty patients in the Study PLRXAS01 received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Serious adverse reactions observed in the 40 patients with refractory or relapsed APL enrolled in Study PLRXAS01 included differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 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 arsenic trioxide injection at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received arsenic trioxide injection. Table 5: Adverse Reactions (≥ 5%) in Patients with Relapsed or Refractory APL Who Received Arsenic Trioxide Injection in Study 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 i…