FDA label 33505b2e-e9ee-6501-e063-6294a90af883

WARNING: DIFFERENTIATION SYNDROME AND CARDIAC CONDUCTION ABNORMALITIES Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide injection have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multi-organ dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Temporary discontinuation of arsenic trioxide injection may be required [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 ) ]. Cardiac Conduction Abnormalities: Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a torsade de pointes-type ventricular arrhythmia, which can be fatal. Before initiating therapy, assess the QTc interval, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide injection to patients with ventricular arrhythmia or prolonged QTcF [see Warnings and Precautions ( 5.2 ) ]. WARNING: DIFFERENTIATION SYNDROME AND CARDIAC CONDUCTION ABNORMALITIES See full prescribing information for complete boxed warning. Patients treated with arsenic trioxide injection may develop differentiation syndrome, which can be fatal. If symptoms occur, initiate high-dose steroids immediately and monitor hemodynamics. ( 5.1 ) Arsenic trioxide injection can cause QT interval prolongation and ventricular arrhythmia, which can be fatal. Before administering arsenic trioxide injection, assess the QT interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. Do not administer arsenic trioxide injection to patients with ventricular arrhythmia or prolonged QTcF. ( 2.3 , 5.2 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor hepatic function tests at least twice weekly during arsenic trioxide injection therapy. ( 5.3 ) Carcinogenesis: Arsenic trioxide is a human carcinogen. Monitor patients for the development of second primary malignancies. ( 5.4 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.5 , 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. Symptoms include unexplained fever, dyspnea, hypoxia, 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 hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. At the first signs of differentiation syndrome, interrupt treatment with arsenic trioxide injection and administer dexamethasone 10 mg intravenously twice daily. Continue high-dose steroids until signs and symptoms have abated for at least 3 days [see Dosage and Administration ( 2.2 ) ]. 5.2 Cardiac Conduction Abnormalities Patients treated with arsenic trioxide injection can develop QTc prolongation, torsade de pointes, and complete heart block. In the clinical trial of patients with relapsed or refractory APL treated with arsenic trioxide injection monotherapy, 40% had at least one ECG tracing with 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 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 greater than 500 msec, immediately withhold treatment with arsenic trioxide injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes, resume arsenic trioxide injection at a reduced dose [see Dosage and Administration ( 2.2 ) ]. 5.3 Hepatotoxicity During treatment with arsenic trioxide injection, monitor liver chemistries at least 2-3 times per week through recovery from toxicities. Withhold treatment with arsenic trioxide injection if elevations in AST), alkaline phosphatase, and/or serum bilirubin occur to greater than 5 times the upper limit of normal [see Dosage and Administration ( 2.2 ) ]. Long-term liver abnormalities can occur in APL patients treated with arsenic trioxide injection. 5.4 Carcinogenesis The active ingredient of arsenic trioxide injection, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies. 5.5 Embryo-Fetal Toxicity 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/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 and males of reproductive potential to use effective contraception during and after treatment with arsenic trioxide injection [see Use in Specific Populations ( 8.1 , 8.3 )].

6 ADVERSE REACTIONS The following serious 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 ) ] Hepatotoxicity [see Warnings and Precautions ( 5.3 ) ] Carcinogenesis [see Warnings and Precautions ( 5.4 ) ] Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.5 ) ] The most common adverse reactions (greater than 30%) were leukocytosis, neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, abdominal pain, hepatic toxicity, fever, rigors, fatigue, insomnia, tachycardia, QTc prolongation, edema, hyperglycemia, hypokalemia, hypomagnesemia, dyspnea, cough, rash or itching, sore throat, arthralgia, headaches, paresthesia, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact STI Pharma LLC, Inc. at 1-888-301-9680 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 6.2 Postmarketing Experience6.2 Postmarketing Experience The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. Cardiac disorders: Ventricular extrasystoles in association with QT prolongation, and ventricular tachycardia in association with QT prolongation. including torsade de pointes, atrioventricular block, and congestive heart failure Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion Hematologic disorders: Pancytopenia, bone marrow necrosis Infections and infestations: Herpes zoster Investigations: Gamma-glutamyltransferase increased Musculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysis Respiratory, thoracic, and mediastinal disorders: Differentiation syndrome, like retinoic acid syndrome, has been reported with the use of arsenic trioxide injection for the treatment of malignancies other than APL [see Boxed Warning]. Ear and labyrinth disorders: Deafness Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis