Drug Class Description
Other antineoplastic agents

Generic Name
Arsenic trioxide

Drug Description
One ml of TRISENOX contains 1 mg of Arsenic trioxide

Presentation
Concentrate for solution for infusionSterile, clear, colourless, aqueous solution.

Indications
TRISENOX is indicated for induction of remission and consolidation in adult patients with relapsed/refractory acute promyelocytic leukaemia (APL), characterised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha) gene. Previous treatment should have included a retinoid and chemotherapy.The response rate of other acute myelogenous leukaemia subtypes to TRISENOX has not been examined.

Adult Dosage
PosologyTRISENOX must be administered under the supervision of a physician who is experienced in the management of acute leukaemias. The same dose is recommended for children, adults, and elderly.Induction treatment schedule: TRISENOX must be administered intravenously at a fixed dose of 0.15 mg/kg/day given daily until the bone marrow remission is achieved (less than 5% blasts present in cellular bone marrow with no evidence of leukaemic cells). If bone marrow remission has not occurred by day 50, dosing must be discontinued.Consolidation schedule: Consolidation treatment must begin 3 to 4 weeks after completion of induction therapy. TRISENOX is to be administered intravenously at a dose of 0.15 mg/kg/day for 25 doses given 5 days per week, followed by 2 days interruption, repeated for 5 weeks.Paediatric use: The experience in children is limited. Of 7 patients under 18 years of age (range 5 to 16 years) treated with TRISENOX at the recommended dose of 0.15 mg/kg/day, 5 patients achieved a complete response. Safety and effectiveness in paediatric patients under 5 years of age have not been studied.Patients with hepatic and/or renal impairment:Since limited data are available across all hepatic impairment groups and across all renal impairment groups, caution is advised in the use of TRISENOX in patients with hepatic and/or renal impairment.Method of administrationTRISENOX must be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required. Patients must be hospitalised at the beginning of treatment due to symptoms of disease and to ensure adequate monitoring.

Child Dosage
Paediatric use: The experience in children is limited. Of 7 patients under 18 years of age (range 5 to 16 years) treated with TRISENOX at the recommended dose of 0.15 mg/kg/day, 5 patients achieved a complete response. Safety and effectiveness in paediatric patients under 5 years of age have not been studied.

Contra Indications
Hypersensitivity to the active substance or any of the excipients.

Special Precautions
Clinically unstable APL patients are especially at risk and will require more frequent monitoring of electrolyte and glycaemia levels as well as more frequent haematologic, hepatic, renal and coagulation parameter tests.Leukocyte Activation Syndrome (APL Differentiation Syndrome): Twenty-five percent of patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukaemia (RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously twice a day) must be immediately initiated, irrespective of the leukocyte count and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome. It is recommended that chemotherapy not be added to treatment with steroids since there is no experience with administration of both steroids and chemotherapy during treatment of the leukocyte activation syndrome due to TRISENOX. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancy. Monitoring and management for these patients should be as described above.Electrocardiogram (ECG) Abnormalities: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. Previous treatment with anthracyclines may increase the risk of QT prolongation. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products (such as class Ia and III antiarrythmics (e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazine), antidepressants (e.g. amitriptyline), some macrolides (e.g. erythromycin), some antihistamines (e.g. terfenadine and astemizole), some quinolone antibiotics (e.g. sparfloxacin), and other individual drugs known to increase QT interval (e.g. cisapride)), a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, amphotericin B or other conditions that result in hypokalemia or hypomagnesaemia. In clinical trials, 40% of patients treated with TRISENOX experienced at least one QT corrected (QTc) interval prolongation greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned to baseline by the end of 8 weeks after TRISENOX infusion. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.ECG and Electrolyte Monitoring Recommendations: Prior to initiating therapy with TRISENOX, a 12-lead ECG must be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; preexisting electrolyte abnormalities must be corrected and, if possible, medicinal products that are known to prolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or risk factors of torsade de pointes should be monitored with continuous cardiac monitoring (ECG). For QTc greater than 500 msec, corrective measures must be completed and the QTc reassessed with serial ECGs prior to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations must be kept above 4 mEq/l and magnesium concentrations must be kept above 1.8 mg/dl. Patients who reach an absolute QT interval value> 500 msec must be reassessed and immediate action must be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy must be considered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and monitored continuously, serum electrolytes must be assessed, TRISENOX therapy must be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc interval during the infusion. Electrocardiograms must be obtained twice weekly, and more frequently for clinically unstable patients, during induction and consolidation.Dose Modification: Treatment with TRISENOX must be interrupted, adjusted, or discontinued before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria, Version 2 is observed and judged to be possibly related to TRISENOX treatment. Patients who experience such reactions that are considered TRISENOX related must resume treatment only after resolution of the toxic event or after recovery to baseline status of the abnormality that prompted the interruption. In such cases, treatment must resume at 50% of the preceding daily dose. If the toxic event does not recur within 3 days of restarting treatment at the reduced dose, the daily dose can be escalated back to 100% of the original dose. Patients who experience a recurrence of toxicity must be removed from treatment.Laboratory tests: The patient's electrolyte and glycaemia levels, as well as haematologic, hepatic, renal and coagulation parameter tests must be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.Patients with renal impairment:Since limited data are available across all renal impairment groups, caution is advised in the use of TRISENOX in patients with renal impairment. The experience in patients with severe renal impairment is insufficient to determine if dose adjustment is required.The use of TRISENOX in patients on dialysis has not been studied.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. The experience in patients with severe hepatic impairment is insufficient to determine if dose adjustment is required..Elderly patients: There is limited clinical data on the use of TRISENOX in the elderly population. Caution is needed in these patients.Hyperleukocytosis: Treatment with TRISENOX has been associated with the development of hyperleukocytosis ( 10 x 103/μl) in some patients. There did not appear to be a relationship between baseline white blood cell (WBC) counts and development of hyperleukocytosis nor did there appear to be a correlation between baseline WBC count and peak WBC counts. Hyperleukocytosis was never treated with additional chemotherapy and resolved on continuation of TRISENOX. WBC counts during consolidation were not as high as during induction treatment and were < 10 x 103/μl, except in one patient who had a WBC count of 22 x 103/μl during consolidation. Twenty patients (50%) experienced leukocytosis; however, in all these patients, the WBC count was declining or had normalized by the time of bone marrow remission and cytotoxic chemotherapy or leukopheresis was not required.

Interactions
No formal assessments of pharmacokinetic interactions between TRISENOX and other therapeutic medicinal products have been conducted. QT/QTc prolongation is expected during treatment with TRISENOX, and torsade de pointes and complete heart block have been reported. Patients who are receiving, or who have received, medicinal products known to cause hypokalemia or hypomagnesaemia, such as diuretics or amphotericin B, may be at higher risk for torsade de pointes. Caution is advised when TRISENOX is coadministered with other medicinal products known to cause QT/QTc interval prolongation such as macrolide antibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalemia or hypomagnesaemia. Additional information about QT prolonging medicinal agents. The influence of TRISENOX on the efficacy of other antileukaemic medicinal products is unknown.

Adverse Reactions
Related adverse reactions of CTC grade 3 and 4 occurred in 37% of patients in clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leukocytosis occurred in 50% of patients with APL, as determined by haematology assessments, rather than adverse event reports.Serious adverse reactions were common (1-10%) and not unexpected in this population. Those serious adverse reactions attributed to TRISENOX included APL differentiation syndrome (3), leukocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrial fibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related to haemorrhage, infections, pain, diarrhoea, nausea.In general, treatmentemergent adverse events tended to decrease over time, perhaps accounted for by amelioration of the underlying disease process. Patients tended to tolerate consolidation and maintenance treatment with less toxicity than in induction. This is probably due to the confounding of adverse events by the uncontrolled disease process early on in the treatment course and the myriad concomitant medicinal products required to control symptoms and morbidity.The table below lists the related grade 3 and 4 adverse drug reactions for the 107 patients treated with TRISENOX in clinical trials (frequencies defined as: common 1/100 to <1/10, uncommon 1/1,000 to < 1/100).Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System Organ ClassCommonUncommonBlood and lymphatic system disordersNeutropeniaThrombocytopeniaFebrile neutropeniaLeucocytosisLeucopeniaMetabolism and nutrition disordersHyperglycaemiaHypokalaemiaHypermagnesaemiaHypernatraemiaKetoacidosisNervous system disordersParaesthesiaCardiac disordersPericardial effusionTachycardiaVascular disordersVasculitisRespiratory, thoracic and mediastinal disordersPleuritic painDyspnoeaPulmonary alveolar haemorrhagePleural effusionHypoxiaGastrointestinal disordersDiarrhoeaSkin and subcutaneous tissue disordersPruritusErythemaMusculoskeletal and connective tissue disordersBone painArthralgiaMyalgiaGeneral disorders and administration site conditionsPyrexiaFatigueChest painPainInvestigationsECG QT prolongedALT increasedAspartate amino transferase increasedHyperbilirubinaemiaHypomagnesaemiaDuring TRISENOX treatment, 13 of the 52 patients in the APL studies had one or more symptoms of APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis (see Section 4.4). Twenty-seven patients had leukocytosis (WBC 10 x 103/μl) during induction, 4 of whom had values above 100,000/μl. Baseline white blood cell (WBC) counts did not correlate with development of leukocytosis on study, and WBC counts during consolidation therapy were not as high as during induction. In these studies, leukocytosis was not treated with chemotherapeutic medicinal products. Medicinal products that are used to lower the white blood cell count often exacerbate the toxicities associated with leukocytosis, and no standard approach has proven effective. One patient treated under a compassionate use program died from cerebral infarct due to leukocytosis, following treatment with chemotherapeutic medicinal products to lower WBC count. Observation is the recommended approach with intervention only in selected cases.Mortality in the pivotal studies from disseminated intravascular coagulation (DIC) associated haemorrhage was very common (> 10%), which is consistent with the early mortality reported in the literature.Arsenic trioxide can cause QT interval prolongation (see Section 4.4). QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemia or hypomagnesaemia. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide. She went onto consolidation without further evidence of QT prolongation.Peripheral neuropathy, characterised by paresthesia/dysesthesia, is a common and well known effect of environmental arsenic. Only 2 patients discontinued treatment early due to this adverse event and one went on to receive additional TRISENOX on a subsequent protocol. Forty-four percent of patients experienced symptoms that could be associated with neuropathy; most were mild to moderate and were reversible upon cessation of treatment with TRISENOX.The following adverse events have been identified during the post-approval use of TRISENOX and have been included following consideration of the observed frequency, seriousness and possible causal relationship to TRISENOX. They are listed below by system organ class and frequency (frequencies are defined as: uncommon (1/1,000 to <1/100), not known (cannot be estimated from the available data).System Organ ClassUncommonNot knownInfection and InfestationsSepsisPneumoniaHerpes zosterBlood and Lymphatics System DisordersAnaemiaPancytopeniaMetabolism and Nutrition DisordersDehydrationFluid retentionPsychiatric DisordersConfusional stateNervous System DisordersConvulsionsDizzinessEye DisordersVision blurredCardiac DisordersCardiac failureVentricular tachycardiaVentricular extrasystolesVascular DisordersHypotensionRespiratory, Thoracic and Mediastinal DisordersPneumonitisDifferentiation syndromeGastrointestinal DisordersVomitingAbdominal painSkin and Subcutaneous DisordersFace oedemaRashRenal and Urinary DisordersRenal failureGeneral Disorders and Administration Site ConditionsOedemaChillsInvestigationsBlood creatinine increasedWeight increasedIn post marketing experience, a differentiation syndrome, like retinoic acid syndrome, has also been reported for the treatment of malignancies other than APL with TRISENOX.

Manufacturer
Cephalon

Drug Availability
(POM)

Updated
26 May 2009