Data from FDA - Curated by EPG Health - Last updated 22 November 2019

Indication(s)

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.

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contraindications
4 CONTRAINDICATIONS TRISENOX is contraindicated in patients who are hypersensitive to arsenic. Hypersensitivity to arsenic. (4)
Adverse reactions
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)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.6)] 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 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 evaluation of TRISENOX in combination with tretinoin is based on results from a randomized trial comparing TRISENOX plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL (Study APL0406) [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. 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. Serious adverse reactions reported in 25% on the TRISENOX/ tretinoin arm and 24% on the chemotherapy/tretinoin arm. The serious adverse reactions reported in ≥ 2% of patients receiving TRISENOX/tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections. Selected hematologic and nonhematologic toxicities that occurred during induction or consolidation are presented in Table 4 for the 129 patients treated with TRISENOX plus tretinoin and the 137 patients treated with chemotherapy plus tretinoin. Table 4: Selected Adverse Reactions of Trisenox in Combination with Tretinoin in Patients with Newly-Diagnosed APL 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 Phase 2 study received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Most patients experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy. SAEs, Grade ≥3 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to TRISENOX in the Phase 2 study of 40 patients with refractory or relapsed APL included APL 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). Table 5 describes the adverse reactions that were observed in ≥ 5% patients, between the ages of 5-73 years, treated for APL with TRISENOX at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received TRISENOX. Table 5: Adverse Reactions (Any Grade) Occurring in ≥ 5% of Patients Treated with TRISENOX Monotherapy for Relapsed or Refractory APL 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 Leukocytosis: TRISENOX in combination with tretinoin 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. Hyperleukocytosis due to TRISENOX may warrant treatment with hydroxyurea [see Dosage and Administration (2.2)]. 6.2 Postmarketing Experience The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are voluntarily reported from a population of unknown size, precise estimates of frequency or causal relationship to drug exposure cannot always be made. 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 Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernicke’s encephalopathy, posterior reversible encephalopathy syndrome 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 TRISENOX for the treatment of malignancies other than APL. Ear and labyrinth disorders: Deafness Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Newly-diagnosed low-risk APL: Induction: 0.15 mg/kg intravenously daily in combination with tretinoin until bone marrow remission. Do not exceed 60 days of induction. (2.1) Consolidation: 0.15 mg/kg intravenously daily 5 days per week during weeks 1-4 of an 8-week cycle for a total of 4 cycles in combination with tretinoin. (2.1) Relapsed or refractory APL: Induction: 0.15 mg/kg intravenously daily until bone marrow remission. Do not exceed 60 days for total induction. (2.2) Consolidation: 0.15 mg/kg intravenously daily for 25 doses over a period up to 5 weeks. (2.2) 2.1 Recommended Dosage 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 dose of TRISENOX is 0.15 mg/kg intravenously daily in combination with tretinoin until bone marrow remission and not to exceed 60 days (see Table 1). For the consolidation cycles, the recommended dose of TRISENOX is 0.15 mg/kg intravenously daily 5 days per week during weeks 1-4 of an 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 Dose 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 Tretinoina 22.5 mg/m2 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 -- -- -- -- Tretinoina 22.5 mg/m2 twice daily orally Days 1-7 Days 1-7 -- -- Daysb 1-7 Daysb 1-7 -- -- aRounded to the nearest 10 mg increment bOmitted 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 therapy with TRISENOX and tretinoin is recommended. Relapsed or Refractory APL A treatment course including TRISENOX monotherapy 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 dose of TRISENOX is 0.15 mg/kg intravenously daily until bone marrow remission or up to a maximum of 60 days. For the consolidation cycle, the recommended dose of TRISENOX is 0.15 mg/kg intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction therapy. 2.2 Dose Modifications for Toxicities During induction therapy, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor at least weekly. Management of some adverse reactions may require dose interruption, dose reduction, or permanent discontinuation of TRISENOX [see Warnings and Precautions (5) and Adverse Reactions (6)]. Table 2 shows the dose modifications for toxicity due to TRISENOX when used alone or in combination with tretinoin. Table 2: Dose Adjustments for Adverse Reactions Adverse Reaction(s) Dose 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 Temporarily withhold TRISENOX. Consider holding tretinoin if symptoms are severe. Treat with 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 7 days in the absence of recurrence of symptoms of differentiation syndrome. If symptoms re-appear, decrease TRISENOX and/or tretinoin to the previous dose. QTc Prolongation greater than 450 msec for men or greater than 460 msec for women: Withhold treatment with TRISENOX and any medication known to prolong the QTc interval. Replete electrolytes. After the QTc normalizes, resume treatment with TRISENOX at a 50% reduced dose (0.075 mg/kg once daily) for 7 days. If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase the dose of TRISENOX to 0.11 mg/kg once daily for 7 days. The dose of TRISENOX can be increased to 0.15 mg/kg 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 Withhold treatment with 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 7 days 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 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 Reduce the dose of TRISENOX and/or tretinoin by 1 dose level (see Table 3 below). Leukocytosis (WBC count greater than 10 Gi/L) 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 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/m2 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 2.3 Instructions for Preparation and Intravenous 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, TRISENOX is chemically and physically stable when stored for 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 intravenously 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. Unused portions of each vial should be discarded properly. Do not mix TRISENOX with other medications. Safe Handling Procedures TRISENOX is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with TRISENOX; dose reduction may be warranted. (8.6) Hepatic Impairment: Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with TRISENOX. (8.7) 8.1 Pregnancy Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, TRISENOX 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 (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/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis. There are no studies with the use of TRISENOX 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 2-4% and 15-20%, 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/m² 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/m² 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/m² basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters. 8.2 Lactation Risk Summary Arsenic trioxide is excreted in human milk. There is no information on the effects of arsenic trioxide on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child from TRISENOX, discontinue breastfeeding during treatment with TRISENOX and for two weeks after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing TRISENOX can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment with TRISENOX [see Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential to use effective contraception during and after treatment with TRISENOX and for six months after the final dose. Males Advise males with female sexual partners of reproductive potential to use effective contraception during and after treatment with TRISENOX and for three months after the final dose. Infertility Males Based on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, TRISENOX may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of TRISENOX in combination with tretinoin in pediatric patients has not been established. The safety and efficacy of TRISENOX as a single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: 5 to 16 years) were treated with TRISENOX at the recommended dose of 0.15 mg/kg/day. A literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from 4 to 21 years. No differences in efficacy and safety were observed by age. 8.5 Geriatric Use Use of TRISENOX in combination with tretinoin in newly-diagnosed adult patients with low-risk APL is supported by a randomized, controlled trial that included 16 patients between the ages of 60 and 70 years. No differences in efficacy and safety were observed by age. A literature review included an additional 77 patients treated with arsenic trioxide in combination with tretinoin as part of induction and consolidation therapy for low and high risk APL, with ages ranging from 60 to 84 years. These studies showed lower survival rates in older patients. Monitor elderly patients frequently during treatment with TRISENOX. The safety and efficacy of TRISENOX as a single agent in older patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Six patients age 65 and above (age range: 65 to 73 years) were treated with TRISENOX at the recommended dose. A literature review included an additional 4 patients treated with arsenic trioxide for relapsed or refractory APL with ages ranging from 69 to 72 years. No differences in efficacy and safety were observed by age. 8.6 Patients with Renal Impairment Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied. 8.7 Patients with Hepatic Impairment Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.
Pregnancy and lactation
8.3 Females and Males of Reproductive Potential Pregnancy Testing TRISENOX can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment with TRISENOX [see Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential to use effective contraception during and after treatment with TRISENOX and for six months after the final dose. Males Advise males with female sexual partners of reproductive potential to use effective contraception during and after treatment with TRISENOX and for three months after the final dose. Infertility Males Based on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, TRISENOX may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

Interactions

7 DRUG INTERACTIONS Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and TRISENOX may increase the risk of serious QT/QTc interval prolongation. Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while patient is using TRISENOX. 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. Avoid concomitant administration of drugs that can lead to electrolyte abnormalities. Monitor electrolytes more frequently in patients who must receive concomitant use of these drugs and TRISENOX. Drugs That Can Lead to Hepatotoxicity Concomitant use of these drugs and TRISENOX, particularly when given in combination with tretinoin, may increase the risk of serious hepatotoxicity. Discontinue or replace with an alternative drug that does not cause hepatotoxicity while the patient is using TRISENOX. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.

More information

Category Value
Authorisation number NDA021248
Agency product number S7V92P67HO
Orphan designation No
Product NDC 63459-600
Date Last Revised 29-08-2019
Type HUMAN PRESCRIPTION DRUG
RXCUI 829926
Marketing authorisation holder Cephalon, Inc.
Warnings WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKE’S Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with TRISENOX 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 TRISENOX 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 TRISENOX to patients with ventricular arrhythmia or prolonged QTcF [see Warnings and Precautions (5.2)]. Encephalopathy: Serious encephalopathy, including Wernicke’s, has occurred in patients treated with TRISENOX. Wernicke’s is a neurologic emergency. Consider testing thiamine levels in patients at risk for thiamine deficiency. Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving TRISENOX. If encephalopathy is suspected, immediately interrupt TRISENOX and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Warnings and Precautions (5.3)]. WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ENCEPHALOPATHY INCLUDING WERNICKE’S See full prescribing information for complete boxed warning. Patients treated with TRISENOX may develop differentiation syndrome, which can be fatal. If symptoms occur, initiate high-dose steroids immediately and monitor hemodynamics. (5.1) TRISENOX can cause QT interval prolongation and ventricular arrhythmia, which can be fatal. Before administering TRISENOX, assess the QT interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTcF. (2.3, 5.2) Encephalopathy including Wernicke’s encephalopathy (WE) occurred in patients receiving TRISENOX. If Wernicke’s encephalopathy is suspected, immediately interrupt TRISENOX treatment and initiate parenteral thiamine. (5.3)