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Trisenox is a brand name for Arsenic Trioxide. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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…
Verbatim from this product's FDA label. Tap a section to expand.
15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission. Do not exceed 60 days. 15 mg/kg/day intravenously daily for 5 days per week during weeks 1-4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin.
15 mg/kg/day intravenously daily until bone marrow remission. Do not exceed 60 days. 15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. 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.
15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission but not to exceed 60 days (see Table 1). 15 mg/kg/day intravenously daily 5 days per week during weeks 1-4 of each 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. 5 mg/kg daily from day 1 until the end of induction cycle with TRISENOX and tretinoin is recommended. 2 )] . 15 mg/kg/day intravenously daily until bone marrow remission or up to a maximum of 60 days.
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. 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 TRISENOX when used alone or in combination with tretinoin. 1 )] Temporarily withhold TRISENOX.
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 TRISENOX and/or tretinoin to the previous dose.
1 ). gov/medwatch . 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.
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.
5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin.
Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. 4 ) Carcinogenesis : Arsenic trioxide is a human carcinogen. Monitor patients for the development of second primary malignancies.
5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. 1 Differentiation Syndrome Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with TRISENOX.
In clinical trials, 16-23% of patients treated with TRISENOX 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. 1 )] . 3 )] . 2 Cardiac Conduction Abnormalities Patients treated with TRISENOX 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 TRISENOX 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 TRISENOX 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 TRISENOX infusion, and it usually resolved by 8 weeks after TRISENOX infusion.
4 CONTRAINDICATIONS TRISENOX is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic. ( 4 )
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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2 )] Withhold TRISENOX and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. 075 mg/kg/day daily) for one week after resolution. 1 )] . 15 mg/kg/day in the absence of QTc prolongation during that 14-day dose-escalation period.
4 )] Withhold TRISENOX and/or tretinoin. 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 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 [see Adverse Reactions ( 6 )] Reduce the dose of TRISENOX and/or tretinoin by 1 dose level (see Table 3 below). 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 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). 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 TRISENOX 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 TRISENOX as an intravenous infusion 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.
Discard unused portions of each vial properly. Do not mix TRISENOX with other medications. Safe Handling Procedures TRISENOX is a hazardous drug. Follow applicable special handling and disposal procedures. 1
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 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 Other Clinically Relevant Adverse Reactions Leukocytosis TRISENOX 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.
2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TRISENOX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
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 Ear and labyrinth disorders: Deafness Hematologic disorders: Pancytopenia, bone marrow necrosis Infections: Herpes zoster Investigations: Gamma-glutamyltransferase increased Musculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysis Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernicke's encephalopathy, posterior reversible encephalopathy syndrome Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis
There are no data on the effect of TRISENOX 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 TRISENOX 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 TRISENOX, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval.
Do not administer TRISENOX 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 )] .
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 TRISENOX and any medication known to prolong the QTc interval.
Correct electrolyte abnormalities. 3 )] . 3 Encephalopathy Serious encephalopathies were reported in patients receiving TRISENOX. 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 TRISENOX. Wernicke’s encephalopathy is a neurologic emergency that can be prevented and treated with thiamine.
, 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 TRISENOX.
If Wernicke’s encephalopathy is suspected, immediately interrupt TRISENOX and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize. 4 Hepatotoxicity In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin.
These abnormalities resolved with temporary discontinuation of TRISENOX and/or tretinoin. Long-term liver abnormalities can occur in patients with APL treated with TRISENOX 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 TRISENOX, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. 3 )] . 5 Carcinogenesis The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen.
Monitor patients for the development of second primary malignancies. 6 Embryo-Fetal Toxicity 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/m 2 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/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 basis.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRISENOX and for 6 months after the last dose. 3 )] .
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