arsenic trioxide: prescribing information – dosing, contraindications, interactions, side effects

TRISENOX is indicated for induction of remission, and consolidation in adult patients with:
- Newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (APL) (white blood cell count, ≤ 10 x 103/µl) in combination with all-trans-retinoic acid (ATRA)
- Relapsed/refractory acute promyelocytic leukaemia (APL) (previous treatment should have included a retinoid and chemotherapy) characterised by the presence of the t(15;17) translocation and/or the presence of the promyelocytic leukaemia/retinoic-acid-receptor-alpha (PML/RAR-alpha) gene.

The response rate of other acute myelogenous leukaemia subtypes to arsenic trioxide has not been examined.

TRISENOX must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and the special monitoring procedures described in section 4.4 must be followed.

Posology

The same dose is recommended for adults and elderly.

Newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (APL)

Induction treatment schedule
TRISENOX must be administered intravenously at a dose of 0.15 mg/kg/day, given daily until complete remission is achieved. If complete remission has not occurred by day 60, dosing must be discontinued.

Consolidation schedule
TRISENOX must be administered intravenously at a dose of 0.15 mg/kg/day, 5 days per week.
Treatment should be continued for 4 weeks on and 4 weeks off, for a total of 4 cycles.

Relapsed/refractory acute promyelocytic leukaemia (APL)

Induction treatment schedule
TRISENOX must be administered intravenously at a fixed dose of 0.15 mg/kg/day given daily until complete remission is achieved (less than 5 % blasts present in cellular bone marrow with no evidence of leukaemic cells). If complete 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.

Dose delay, modification and reinitiation

Treatment with TRISENOX must be temporarily interrupted before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria 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 7 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.
For ECG, electrolytes abnormalities and hepatotoxicity see section 4.4.

Special populations

Hepatic impairment
Since no data are available across all hepatic impairment groups and hepatotoxic effects may occur during the treatment with TRISENOX, caution is advised in the use of TRISENOX in patients with hepatic impairment (see section 4.4 and 4.8).

Renal impairment
Since no data are available across all renal impairment groups, caution is advised in the use of TRISENOX in patients with renal impairment.

Paediatric population
The safety and efficacy of TRISENOX in children aged up to 17 years has not been established.
Currently available data for children aged 5 to 16 years are described in section 5.1 but no recommendation on a posology can be made. No data are available for children under 5 years.

Method of administration

TRISENOX 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.

For instructions on preparation of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile
Related adverse reactions of CTC grade 3 and 4 occurred in 37 % of relapsed/refractory APL patients in clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leucocytosis occurred in 50 % of patients with relapsed/refractory APL, as determined by haematology assessments.

Serious adverse reactions were common (1-10 %) and not unexpected in the relapsed/refractory population. Those serious adverse reactions attributed to arsenic trioxide included APL differentiation syndrome (3), leucocytosis (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, treatment-emergent adverse events tended to decrease over time, in relapsed/refractory APL patients 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.

In a phase 3, multicentre, non-inferiority trial comparing all-trans-retinoic acid (ATRA) plus chemotherapy with ATRA plus arsenic trioxide in newly diagnosed low-to-intermediate risk APL patients (Study APL0406; see also section 5.1), serious adverse reactions including hepatic toxicity, thrombocytopenia, neutropenia and QTc prolongation were observed in patients treated with arsenic trioxide.

Tabulated list of adverse reactions
The following undesirable effects have been reported in clinical trials and/or post-marketing experience in newly diagnosed and relapsed/refractory APL patients. Undesirable effects are listed in table 2 below as MedDRA preferred term by system organ class and frequencies observed during TRISENOX clinical trials in 52 patients with refractory/relapsed APL. Frequencies are defined as:
(very common ≥ 1/10), (common ≥ 1/100 to < 1/10), (uncommon ≥ 1/1,000 to < 1/100), not known (cannot be estimated from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2

All grades
Grades ≥ 3
Infections and infestations
Herpes zoster
Common
Not known
Sepsis
Not known
Not known
Pneumonia
Not known
Not known
Blood and lymphatic system disorders
Febrile neutropenia
Common
Common
Leucocytosis
Common
Common
Neutropenia
Common
Common
Pancytopenia
Common
Common
Thrombocytopenia
Common
Common
Anaemia
Common
Not known
Leukopenia
Not known
Not known
Lymphopenia
Not known
Not known
Metabolism and nutrition disorders
Hyperglycaemia
Very Common
Very Common
Hypokalaemia
Very Common
Very Common
Hypomagnesaemia
Very Common
Common
Hypernatraemia
Common
Common
Ketoacidosis
Common
Common
Hypermagnesaemia
Common
Not known
Dehydration
Not known
Not known
Fluid retention
Not known
Not known
Psychiatric disorders
Confusional state
Not known
Not known
Nervous system disorders
Paraesthesia
Very Common
Common
Dizziness
Very Common
Not known
Headache
Very Common
Not known
Convulsion
Common
Not known

All grades
Grades ≥ 3
Encephalopathy, Wernicke encephalopathy
Not known
Not known
Eye disorders
Vision blurred
Common
Not known
Cardiac disorders
Tachycardia
Very Common
Common
Pericardial effusion
Common
Common
Ventricular extrasystoles
Common
Not known
Cardiac failure
Not known
Not known
Ventricular tachycardia
Not known
Not known
Vascular disorders
Vasculitis
Common
Common
Hypotension
Common
Not known
Respiratory, thoracic and mediastinal disorders
Differentiation syndrome
Very Common
Very Common
Dyspnoea
Very Common
Common
Hypoxia
Common
Common
Pleural effusion
Common
Common
Pleuritic pain
Common
Common
Pulmonary alveolar haemorrhage
Common
Common
Pneumonitis
Not known
Not known
Gastrointestinal disorders
Diarrhoea
Very Common
Common
Vomiting
Very Common
Not known
Nausea
Very Common
Not known
Abdominal pain
Common
Common
Skin and subcutaneous tissue disorders
Pruritus
Very Common
Not known
Rash
Very Common
Not known
Erythema
Common
Common
Face oedema
Common
Not known
Musculoskeletal and connective tissue disorders
Myalgia
Very Common
Common
Arthralgia
Common
Common
Bone pain
Common
Common
Renal and urinary disorders
Renal failure
Common
Not known
General disorders and administration site conditions
Pyrexia
Very Common
Common
Pain
Very Common
Common
Fatigue
Very Common
Not known
Oedema
Very Common
Not known
Chest pain
Common
Common
Chills
Common
Not known
Investigations
Alanine amino transferase increased
Very Common
Common
Aspartate amino transferase increased
Very Common
Common
Electrocardiogram QT prolonged
Very Common
Common
Hyperbilirubinaemia
Common
Common
Blood creatinine increased
Common
Not known
Weight increased
Common
Not known
Gamma-glutamyltransferase increased*
Not known*
Not known*

*In the CALGB study C9710, 2 cases of grade ≥3 increased GGT were reported out of the 200 patients who received TRISENOX consolidation cycles (cycle 1 and cycle 2) versus none in the control arm.

Description of selected adverse reactions

Differentiation syndrome
During TRISENOX treatment, 14 of the 52 patients in the APL studies in the relapsed setting 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 leucocytosis (see section 4.4). Twenty-seven patients had leucocytosis (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 leucocytosis on study, and WBC counts during consolidation therapy were not as high as during induction. In these studies, leucocytosis 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 leucocytosis, and no standard approach has proven effective. One patient treated under a compassionate use program died from cerebral infarct due to leucocytosis, 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 in the relapsed setting from disseminated intravascular coagulation (DIC) associated haemorrhage was very common (> 10 %), which is consistent with the early mortality reported in the literature.

In newly diagnosed patients with low to intermediate risk APL, differentiation syndrome was observed in 19 % including 5 severe cases.

In post marketing experience, a differentiation syndrome, like retinoic acid syndrome, has also been reported for the treatment of malignancies other than APL with TRISENOX.

QT interval prolongation
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, pre-existing 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.

In newly diagnosed patients, with low to intermediate risk APL, QTc prolongation was observed in 15.6 %. In one patient induction treatment was terminated because of severe prolongation of the QTc interval and electrolyte abnormalities on day 3.

Peripheral neuropathy
Peripheral neuropathy, characterised by paraesthesia/dysaesthisia, is a common and well known effect of environmental arsenic. Only 2 relapsed/refractory APL patients discontinued treatment early due to this adverse event and one went on to receive additional TRISENOX on a subsequent protocol.
Forty-four per cent of relapsed/refractory APL patients experienced symptoms that could be associated with neuropathy; most were mild to moderate and were reversible upon cessation of treatment with TRISENOX.

Hepatotoxicity (grade 3-4)
In newly diagnosed patients with low to intermediate risk APL 63.2 % developed grade 3 or 4 hepatic toxic effects during induction or consolidation treatment with TRISENOX in combination with ATRA. However, toxic effects resolved with temporary discontinuation of either TRISENOX, ATRA or both (see section 4.4).

Haematological and gastrointestinal toxicity
In newly diagnosed patients with low to intermediate risk APL, gastrointestinal toxicity, grade 3-4 neutropenia and grade 3 or 4 thrombocytopenia occurred, however these were 2.2 times less frequent in patients treated with TRISENOX in combination with ATRA compared to patients treated with ATRA + chemotherapy.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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)
27 % of patients with APL, in the relapsed/refractory setting, treated with arsenic trioxide 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 leucocytosis. This syndrome can be fatal. In newly diagnosed APL patients treated with arsenic trioxide and all-trans-retinoic acid (ATRA), APL differentiation syndrome was observed in 19 % including 5 severe cases. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), treatment with TRISENOX must be temporarily discontinued and 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. If clinically justified/required, concomitant diuretic therapy is also recommended. The majority of patients do not require permanent termination of TRISENOX therapy during treatment of the APL differentiation syndrome. As soon as signs and symptoms have subsided, treatment with TRISENOX can be resumed at 50 % of the previous dose during the first 7 days. Thereafter, in the absence of worsening of the previous toxicity, TRISENOX might be resumed at full dosage. In the case of the reappearance of symptoms TRISENOX should be reduced to the previous dosage. In order to prevent the development of the APL differentiation syndrome during induction treatment, prednisone (0.5 mg/kg body weight per day throughout induction treatment) may be administered from day 1 of TRISENOX application to the end of induction therapy in APL patients. 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 medicinal products 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 hypokalaemia or hypomagnesaemia. In clinical trials, in the relapsed/refractory setting, 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. In newly diagnosed APL patients 15.6 % showed QTc prolongation with arsenic trioxide in combination with ATRA (see section 4.8). In one newly diagnosed patient induction treatment was terminated because of severe prolongation of the QTc interval and electrolyte abnormalities on day 3 of induction treatment.

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; pre-existing 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 and, if available, a specialist advice could be sought 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. After recovery, treatment should be resumed at 50 % of the preceding daily dose. If QTc prolongation does not recur within 7 days of restarting treatment at the reduced dose, treatment with TRISENOX can be resumed at 0.11 mg/kg body weight per day for a second week. The daily dose can be escalated back to 100 % of the original dose if no prolongation occurs. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion. Electrocardiograms must be obtained twice weekly, and more frequently for clinically unstable patients, during induction and consolidation.

Hepatotoxicity (grade 3 or greater)
In newly diagnosed patients with low to intermediate risk APL 63.2 % developed grade 3 or 4 hepatic toxic effects during induction or consolidation treatment with arsenic trioxide in combination with ATRA (see section 4.8). However, toxic effects resolved with temporary discontinuation of either arsenic trioxide, ATRA or both. Treatment with TRISENOX must be discontinued before the scheduled end of therapy at any time that a hepatotoxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed. As soon as bilirubin and/or SGOT and/or alkaline phosphatase are decreased to below 4 times the normal upper level, treatment with TRISENOX should be resumed at 50 % of the previous dose during the first 7 days. Thereafter, in absence of worsening of the previous toxicity, TRISENOX should be resumed at full dosage. In case of reappearance of hepatotoxicity, TRISENOX must be permanently discontinued.

Dose delay and modification
Treatment with TRISENOX must be temporarily interrupted before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed and judged to be possibly related to TRISENOX treatment. (see section 4.2)

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.

Renal impairment
Since no 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.

Hepatic impairment
Since no data are available across all hepatic impairment groups and hepatotoxic effects may occur during the treatment with arsenic trioxide caution is advised in the use of TRISENOX in patients with hepatic impairment (see section 4.4 on hepatotoxicity and section 4.8). The experience in patients with severe hepatic impairment is insufficient to determine if dose adjustment is required.

Elderly
There is limited clinical data on the use of TRISENOX in the elderly population. Caution is needed in these patients.

Hyperleucocytosis
Treatment with arsenic trioxide has been associated with the development of hyperleucocytosis (≥ 10 x 103/μl) in some relapsed/refractory APL patients. There did not appear to be a relationship between baseline white blood cell (WBC) counts and development of hyperleucocytosis nor did there appear to be a correlation between baseline WBC count and peak WBC counts. Hyperleucocytosis 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 relapsed/refractory APL patients (50 %) experienced leucocytosis; however, in all these patients, the WBC count was declining or had normalized by the time of bone marrow remission and cytotoxic chemotherapy or leucopheresis was not required. In newly diagnosed patients with low to intermediate risk APL leucocytosis developed during induction therapy in 35 of 74 (47 %) patients (see section 4.8). However all cases were successfully managed with hydroxyurea therapy.

In newly diagnosed and relapsed/refractory APL patients who develop sustained leucocytosis after initiation of therapy, hydroxyurea should be administered. Hydroxyurea should be continued at a given dose to keep the white blood cell count ≤ 10 x 103/μl and subsequently tapered.

Table 1 Recommendation for initiation of hydroxyurea
WBC
Hydroxyurea
10–50 x 103/µl
500 mg four times a day
> 50 x 103/µl
1000 mg four times a day

Development of second primary malignancies
The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Encephalopathy
Cases of encephalopathy were reported with treatment with arsenic trioxide. Wernicke encephalopathy after arsenic trioxide treatment was reported in patients with vitamin B1 deficiency. Patients at risk of B1 deficiency should be closely monitored for signs and symptoms of encephalopathy after arsenic trioxide initiation. Some cases recovered with vitamin B1 supplementation.

Excipient with known effect
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

No formal assessments of pharmacokinetic interactions between TRISENOX and other therapeutic medicinal products have been conducted.

Medicinal products known to cause QT/QTc interval prolongation, hypokalaemia or hypomagnesaemia QT/QTc prolongation is expected during treatment with arsenic trioxide, and torsade de pointes and complete heart block have been reported. Patients who are receiving, or who have received, medicinal products known to cause hypokalaemia or hypomagnesaemia, such as diuretics or amphotericin B,

may be at higher risk for torsade de pointes. Caution is advised when TRISENOX is co-administered with other medicinal products known to cause QT/QTc interval prolongation such as macrolide antibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalaemia or hypomagnesaemia. Additional information about QT prolonging medicinal agents, is provided in section 4.4.

Medicinal products known to cause hepatotoxic effects
Hepatotoxic effects may occur during the treatment with arsenic trioxide, caution is advised when TRISENOX is co-administered with other medicinal products known to cause hepatotoxic effects (see section 4.4 and 4.8).

Other antileukaemic medicinal products
The influence of TRISENOX on the efficacy of other antileukaemic medicinal products is unknown.

Contraception in males and females
Due to the genotoxic risk of arsenic compounds (see section 5.3), women of childbearing potential must use effective contraceptive measures during treatment with TRISENOX and for 6 months following completion of treatment.

Men should use effective contraceptive measures and be advised to not father a child while receiving TRISENOX and for 3 months following completion of treatment.

Pregnancy
Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies (see section 5.3).
There are no studies in pregnant women using TRISENOX.

If this medicinal product is used during pregnancy or if the patient becomes pregnant while taking this product, the patient must be informed of the potential harm to the foetus.

Breast-feeding
Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding infants and children from TRISENOX, breast-feeding must be discontinued prior to and throughout administration and for two weeks after the last dose.

Fertility
No clinical or non-clinical fertility studies have been conducted with TRISENOX.

TRISENOX has no or negligible influence on the ability to drive and use machines.

If symptoms suggestive of serious acute arsenic toxicity (e.g. convulsions, muscle weakness and confusion) appear, TRISENOX must be immediately discontinued and chelating therapy with penicillamine at a daily dose ≤ 1 g per day may be considered. The duration of treatment with penicillamine must be evaluated taking into account the urinary arsenic laboratory values. For patients who cannot take oral medicinal product, dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until any immediately life-threatening toxicity has subsided may be considered. Thereafter, penicillamine at a daily dose ≤ 1 g per day may be given. In the presence of coagulopathy, the oral administration of the chelating agent Dimercaptosuccinic Acid Succimer (DCI) 10 mg/kg or 350 mg/m2 every 8 hours during 5 days and then every 12 hours during 2 weeks is recommended. For patients with severe, acute arsenic overdose, dialysis should be considered

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27

Mechanism of action

The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha (PML/RAR alpha).

Clinical efficacy and safety

Newly diagnosed non high risk APL patients
TRISENOX has been investigated in 77 newly diagnosed patients with low to intermediate risk APL, in a controlled, randomized, non-inferiority Phase 3 clinical study comparing the efficacy and safety of TRISENOX combined with all-trans-retinoic acid (ATRA) with those of ATRA + chemotherapy (eg, idarubicin and mitoxantrone) (Study APL0406). Patients with newly diagnosed APL confirmed by the presence of t(15; 17) or PML-RARα by RT-PCR or micro speckled PML nuclear distribution in leukaemic cells were included. No data are available on patient with variant translocations like t(11;17) (PLZF/RARα). Patients with significant arrhythmias, EKG abnormalities (congenital long QT syndrome, history or presence of significant ventricular or atrial tachyarrhythmia, clinically significant resting bradycardia (< 50 beats per minute), QTc > 450 msec on screening EKG, right bundle branch block plus left anterior hemiblock, bifascicular block) or neuropathy were excluded from the study.
Patients in the ATRA + TRISENOX treatment group received oral ATRA at 45 mg/m2 daily and IV TRISENOX at 0.15 mg/kg daily until CR. During consolidation, ATRA was given at the same dose for periods of 2 weeks on and 2 weeks off for a total of 7 courses, and TRISENOX was given at the

same dose 5 days per week, 4 weeks on and 4 weeks off, for a total of 4 courses. Patients in the ATRA + chemotherapy treatment group received IV idarubicin at 12 mg/m2 on days 2, 4, 6, and 8 and oral ATRA at 45 mg/m2 daily until CR. During consolidation, patients received idarubicin at 5 mg/m2 on days 1 to 4 and ATRA at 45 mg/m2 daily for 15 days, then IV mitoxantrone at 10 mg/m2 on days 1 to 5 and ATRA again at 45 mg/m2 daily for 15 days, and finally a single dose of idarubicin at 12 mg/m2 and ATRA at 45 mg/m2 daily for 15 days. Each course of consolidation was initiated at haematological recovery from the previous course defined as absolute neutrophil count > 1.5 × 109/l and platelets > 100 × 109/l. Patients in the ATRA + chemotherapy treatment group also received maintenance treatment for up to 2 years, consisting of oral 6-mercaptopurine at 50 mg/m2 daily, intramuscular methotrexate at 15 mg/m2 weekly, and ATRA at 45 mg/m2 daily for 15 days every 3 months.

The key efficacy results are summarised in table 3 below:

Table 3
Endpoint
ATRA +
TRISENOX
(n = 77)
[%]
ATRA +
Chemotherapy
(n = 79)
[%]
Confidence interval (CI)

P-value
2-Year event-free survival (EFS)

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (AsIII). AsIII is the pharmacologically active species of arsenic trioxide.

Distribution
The volume of distribution (Vd) for AsIII is large (> 400 l) indicating significant distribution into the tissues with negligible protein binding. Vd is also weight dependent, increasing with increasing body weight. Total arsenic accumulates mainly in the liver, kidney, and heart and, to a lesser extent, in the lung, hair, and nails.

Biotransformation
The metabolism of arsenic trioxide involves oxidation of arsenious acid (AsIII), the active species of arsenic trioxide, to arsenic acid (AsV), as well as oxidative methylation to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by methyltransferases, primarily in the liver. The pentavalent metabolites, MMAV and DMAV, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but due to their longer half-life, accumulate more upon multiple dosing than does AsIII. The extent of accumulation of these metabolites is dependent on the dosing regimen. Approximate accumulation ranged from 1.4- to 8-fold following multiple as compared to single dose administration. AsV is present in plasma only at relatively low levels.

In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11. Substances that are substrates for these P450 enzymes are not expected to interact with TRISENOX.

Elimination
Approximately 15 % of the administered TRISENOX dose is excreted in the urine as unchanged AsIII.
The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine. The plasma