Can Arsenic Trioxide cause diarrhea?

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

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) ] .