Trisenox
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
TRISENOX 1 mg/ml concentrate for solution for infusion 
TRISENOX 2 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
TRISENOX 1 mg/ml concentrate for solution for infusion 
 
Each ml of concentrate contains 1 mg of arsenic trioxide.  
Each ampoule of 10 ml contains 10 mg of arsenic trioxide. 
 
TRISENOX 2 mg/ml concentrate for solution for infusion 
 
Each ml of concentrate contains 2 mg of arsenic trioxide. 
Each vial of 6 ml contains 12 mg of arsenic trioxide. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear, colourless, aqueous solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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. 
 



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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. 



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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.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
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 



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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.  
 



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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’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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, 



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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. 
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
Women of childbearing potential and men must use effective contraception during treatment with 
TRISENOX. 
 
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.  
 
Fertility 
No clinical or non-clinical fertility studies have been conducted with TRISENOX. 
 
4.7 Effects on ability to drive and use machines 
 
TRISENOX has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
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 



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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 the APL0406 study in newly diagnosed 
patients and in clinical trials and/or post-marketing experience in 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 
Encephalopathy, Wernicke 
encephalopathy 

Not known Not known 

Eye disorders 
Vision blurred Common Not known 



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 All grades Grades ≥ 3 
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.  
 



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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/l) during induction, 4 of whom had 
values above 100,000/l. 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 



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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. 
 
4.9 Overdose 
 
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 
 
5.1 Pharmacodynamic 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 



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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) 97 86 

95 % CI for 
the difference, 

2-22 
percentage 

points 

p < 0.001 
for non-inferiority 

 
p = 0.02 

for superiority of 
ATRA + TRISENOX 

Haematologic 
complete remission 
(HCR) 

100 95  p = 0.12 

2-Year overall 
survival (OS) 99 91  p = 0.02 

2-Year disease-free 
survival (DFS) 97 90  p = 0.11 

2-Year cumulative 
incidence of relapse 
(CIR) 

1 6  p = 0.24 

APL = acute promyelocytic leukaemia; ATRA = all-trans-retinoic acid 
 
Relapsed/refractory APL 
TRISENOX has been investigated in 52 APL patients, previously treated with an anthracycline and a 
retinoid regimen, in two open-label, single-arm, non-comparative studies. One was a single 
investigator clinical study (n=12) and the other was a multicentre, 9-institution study (n=40). Patients 
in the first study received a median dose of 0.16 mg/kg/day of TRISENOX (range 0.06 to 
0.20 mg/kg/day) and patients in the multicentre study received a fixed dose of 0.15 mg/kg/day. 
TRISENOX was administered intravenously over 1 to 2 hours until the bone marrow was free of 
leukaemic cells, up to a maximum of 60 days. Patients with complete remission received consolidation 
therapy with TRISENOX for 25 additional doses over a 5 week period. Consolidation therapy began 
6 weeks (range, 3-8) after induction in the single institution study and 4 weeks (range, 3-6) in the 
multicentre study. Complete remission (CR) was defined as the absence of visible leukaemic cells in 
the bone marrow and peripheral recovery of platelets and white blood cells.  
 
Patients in the single centre study had relapsed following 1-6 prior therapy regimens and 2 patients 
had relapsed following stem cell transplantation. Patients in the multicentre study had relapsed 
following 1-4 prior therapy regimens and 5 patients had relapsed following stem cell transplantation. 
The median age in the single centre study was 33 years (age range 9 to 75). The median age in the 
multicentre study was 40 years (age range 5 to 73). 
 
The results are summarised in the table 4 below. 
 



13 

Table 4 
 Single centre trial 

N=12 
Multicentre trial 

N=40 
TRISENOX dose, mg/kg/day 
(median, range) 

0.16 (0.06 – 0.20) 0.15 

Complete remission 11 (92 %) 34 (85 %) 
Time to bone marrow 
remission (median) 

32 days 35 days 

Time to CR (median)  54 days 59 days 
18-Month survival  67 % 66 % 

 
The single institution study included 2 paediatric patients (< 18 years old), both of whom achieved 
CR. The multicentre trial included 5 paediatric patients (< 18 years old), 3 of whom achieved CR. No 
children of less than 5 years of age were treated.  
 
In a follow-up treatment after consolidation, 7 patients in the single institution study and 18 patients in 
the multicentre study received further maintenance therapy with TRISENOX. Three patients from the 
single institution study and 15 patients from the multicentre study had stem cell transplants after 
completing TRISENOX. The Kaplan-Meier median CR duration for the single institution study is 14 
months and has not been reached for the multicentre study. At last follow-up, 6 of 12 patients in the 
single institution study were alive with a median follow-up time of 28 months (range 25 to 29). In the 
multicentre study 27 of 40 patients were alive with a median follow-up time of 16 months (range 
9 to 25). Kaplan-Meier estimates of 18-month survival for each study are shown below. 

0 6 12 18 24 30 36
Months

0%

20%

40%

60%

80%

100%

Single Center
Multicenter Study

At Risk
  12
  40

Deaths
   6

  13

18-Month
67%
66%

 
Cytogenetic confirmation of conversion to a normal genotype and reverse transcriptase - polymerase 
chain reaction (RT-PCR) detection of PML/RAR conversion to normal are shown in table 5 below. 
 



14 

Cytogenetics after TRISENOX therapy 
 
Table 5 
 Single centre pilot trial 

N with CR = 11 
Multicentre trial 
N with CR = 34 

Conventional 
Cytogenetics 
[t(15;17)] 
Absent 
Present 
Not evaluable 

 
 
 

8 (73 %) 
1 (9 %)  

2 (18 %) 

 
 
 

31 (91 %) 
0 % 

3 (9 %) 
RT-PCR for PML/ 
RAR 
 

Negative 
Positive 
Not evaluable 

 
 
 

8 (73 %) 
3 (27 %) 

0 

 
 
 

27 (79 %) 
4 (12 %) 
3 (9 %) 

 
Responses were seen across all age groups tested, ranging from 6 to 75 years. The response rate was 
similar for both genders. There is no experience on the effect of TRISENOX on the variant APL 
containing the t(11;17) and t(5;17) chromosomal translocations. 
 
Paediatric population 
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 (see section 4.2). 
 
5.2 Pharmacokinetic properties 
 
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. 
 



15 

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 
concentration of AsIII declines from peak plasma concentration in a biphasic manner with a mean 
terminal elimination half-life of 10 to 14 hours. The total clearance of AsIII over the single-dose range 
of 7-32 mg (administered as 0.15 mg/kg) is 49 l/h and the renal clearance is 9 l/h. Clearance is not 
dependent on the weight of the subject or the dose administered over the dose range studied. The mean 
estimated terminal elimination half-lives of the metabolites MMAV and DMAV are 32 hours and 
70 hours, respectively. 
 
Renal impairment 
Plasma clearance of AsIII was not altered in patients with mild renal impairment (creatinine clearance 
of 50-80 ml/min) or moderate renal impairment (creatinine clearance of 30-49 ml/min). The plasma 
clearance of AsIII in patients with severe renal impairment (creatinine clearance less than 30 ml/min) 
was 40 % lower when compared with patients with normal renal function (see section 4.4). 
 
Systemic exposure to MMAV and DMAV tended to be larger in patients with renal impairment; the 
clinical consequence of this is unknown but no increased toxicity was noted.  
 
Hepatic impairment 
Pharmacokinetic data from patients with hepatocellular carcinoma having mild to moderate hepatic 
impairment indicate that AsIII or AsV do not accumulate following twice-weekly infusions. No clear 
trend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed with 
decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC. 
 
Linearity/non-linearity 
In the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) 
appears to be linear. The decline from peak plasma concentration of AsIII occurs in a biphasic manner 
and is characterized by an initial rapid distribution phase followed by a slower terminal elimination 
phase. After administration at 0.15 mg/kg on a daily (n=6) or twice-weekly (n=3) regimen, an 
approximate 2-fold accumulation of AsIII was observed as compared to a single infusion. This 
accumulation was slightly more than expected based on single-dose results.  
 
5.3 Preclinical safety data 
 
Limited reproductive toxicity studies of arsenic trioxide in animals indicate embryotoxicity and 
teratogenicity (neural tube defects, anophthalmia and microphthalmia) at administration of 1-10 times 
the recommended clinical dose (mg/m2). Fertility studies have not been conducted with TRISENOX. 
Arsenic compounds induce chromosomal aberrations and morphological transformations of 
mammalian cells in vitro and in vivo. No formal carcinogenicity studies of arsenic trioxide have been 
performed. However, arsenic trioxide and other inorganic arsenic compounds are recognised as human 
carcinogens. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium hydroxide  
Hydrochloric acid (for pH adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, this medicinal product must not be mixed with other 
medicinal products except those mentioned in section 6.6.  
 



16 

6.3 Shelf life 
 
TRISENOX 1 mg/ml concentrate for solution for infusion 
4 years. 
 
TRISENOX 2 mg/ml concentrate for solution for infusion 
3 years. 
 
After dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at 
15-30 °C and 72 hours at refrigerated (2-8 °C) temperatures. From a microbiological point of view, the 
product must be used immediately. If not used immediately, in-use storage times and conditions prior 
to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 °C, 
unless dilution has taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
For storage conditions after dilution of the medicinal products, see section 6.3. 
 
6.5 Nature and contents of container 
 
TRISENOX 1 mg/ml concentrate for solution for infusion 
Type I borosilicate glass ampoule containing 10 ml of concentrate. Each pack contains 10 ampoules. 
 
TRISENOX 2 mg/ml concentrate for solution for infusion 
6 ml concentrate in a clear, Type I borosilicate glass vial with a chlorobutyl rubber stopper (FluroTec 
coated plug) and an aluminium crimp cap with a plastic flip-top button. Each pack contains 10 vials. 
 
6.6 Special precautions for disposal and other handling 
 
Preparation of TRISENOX 
Aseptic technique must be strictly observed throughout handling of TRISENOX since no preservative 
is present. 
 
TRISENOX must be diluted with 100 to 250 ml of glucose 50 mg/ml (5 %) solution for injection or 
sodium chloride 9 mg/ml (0.9 %) solution for injection immediately after withdrawal from the 
ampoule or vial.  
 
TRISENOX must not be mixed with or concomitantly administered in the same intravenous line with 
other medicinal products. 
 
The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually 
for particulate matter and discoloration prior to administration. Do not use the preparation if foreign 
particulate matter is present.  
 
Procedure for proper disposal 
 
TRISENOX is for single use only and any unused portions of each ampoule or of each vial must be 
discarded properly. Do not save any unused portions for later administration. 
 
Any unused medicinal product, any items that come into contact with the product or waste material 
must be disposed of in accordance with local requirements. 
 
 



17 

7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031 GA Haarlem 
Netherlands  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
TRISENOX 1 mg/ml concentrate for solution for infusion 
EU/1/02/204/001 
 
TRISENOX 2 mg/ml concentrate for solution for infusion 
EU/1/02/204/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 05 March 2002 
Date of latest renewal: 05 March 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



19 

A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Almac Pharma Services Limited, 
Almac House,  
20 Seagoe Industrial Estate, 
Craigavon, 
BT63 5QD, 
United Kingdom 
 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate, 
Dundalk, Co. Louth, 
A91 P9KD, 
Ireland 
 
Teva Pharmaceuticals Europe B.V. 
Swensweg 5, 
2031 GA Haarlem,  
The Netherlands 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2) 
 

 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic Safety Update Reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT  
 
 Risk Management Plan (RMP)  

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted:  

 At the request of the European Medicines Agency;  
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



22 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TRISENOX 1 mg/ml concentrate for solution for infusion 
arsenic trioxide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of concentrate contains 1 mg of arsenic trioxide. 
Each ampoule of 10 ml contains 10 mg of arsenic trioxide. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
sodium hydroxide 
hydrochloric acid 
water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
10 ampoules  
10 mg/10 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use after dilution 
Single use only 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: handle with caution 
 
 
8. EXPIRY DATE 
 
EXP  



23 

Read the leaflet for the shelf-life of the diluted product 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031 GA Haarlem 
Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/02/204/001  
 
 
13. BATCH NUMBER 
 
Lot:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



24 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
AMPOULE  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
TRISENOX 1 mg/ml sterile concentrate 
arsenic trioxide 
IV use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
Single use only 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot:  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 mg/10 ml 
 
 
6. OTHER 
 



25 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON FOR THE 2 MG/ML VIAL 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TRISENOX 2 mg/ml concentrate for solution for infusion  
arsenic trioxide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of concentrate contains 2 mg of arsenic trioxide. 
Each vial of 6 ml contains 12 mg of arsenic trioxide. 
 
 
 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium hydroxide, hydrochloric acid, water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
10 vials 
12 mg/6 ml 
 

 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use after dilution 
Single use only 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: handle with caution 
 

NEW CONCENTRATION 



26 

 
8. EXPIRY DATE 
 
EXP  
Read the leaflet for the shelf-life of the diluted product 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 
2031 GA Haarlem 
Netherlands  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/02/204/002 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



27 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 2 MG/ML 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
TRISENOX 2 mg/ml sterile concentrate 
arsenic trioxide 
IV use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
Single use only 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot:  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
12 mg/6 ml 
 
 
6. OTHER 
 
 
 
 
Cytotoxic 
 

NEW CONCENTRATION 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



29 

Package leaflet: Information for the patient 
 

TRISENOX 1 mg/ml concentrate for solution for infusion 
arsenic trioxide 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have further questions, please ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
 
1. What TRISENOX is and what it is used for 
2. What you need to know before you are given TRISENOX 
3. How TRISENOX is given 
4. Possible side effects 
5. How to store TRISENOX 
6. Contents of the pack and other information 
 
 
1. What TRISENOX is and what it is used for 
 
TRISENOX is used in adult patients with newly diagnosed low-to-intermediate risk acute 
promyelocytic leukaemia (APL), and in adult patients, whose disease has not responded to other 
therapies. APL is a unique type of myeloid leukaemia, a disease in which abnormal white blood cells 
and abnormal bleeding and bruising occur. 
 
 
2. What you need to know before you are given TRISENOX 
 
TRISENOX must be given under the supervision of a physician experienced in the treatment of acute 
leukaemias.  
 
You must not receive TRISENOX 
If you are allergic to arsenic trioxide or any of the other ingredients of this medicine (listed in section 
6). 
 
Warnings and precautions 
You must talk to your doctor or nurse before you are given TRISENOX, if 

- you have impaired kidney function. 
- you have any liver problems. 

 
Your doctor will take the following precautions: 

- Tests will be performed to check the amount of potassium, magnesium, calcium and creatinine 
in your blood before your first dose of TRISENOX.  

- You should have an electrical recording of the heart (electrocardiogram ECG) performed before 
your first dose.  

- Blood tests (potassium, calcium, magnesium and liver function) should be repeated during your 
treatment with TRISENOX.  

- In addition, you will receive electrocardiograms twice weekly.  
- If you are at risk for a certain type of abnormal heart rhythm (e.g. torsade de pointes or QTc 

prolongation), your heart will be monitored continuously.  
- Your doctor may monitor your health during and after treatment, since arsenic trioxide, the 

active substance in TRISENOX, may cause other cancers. You should report any new and 
exceptional symptoms and circumstances whenever you see your doctor. 



30 

- Follow-up of your cognitive and mobility functions if you are at risk for vitamin B1 deficiency. 
 
Children and adolescents 
TRISENOX is not recommended in children and adolescents below 18 years of age. 
 
Other medicines and TRISENOX 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 
In particular tell your doctor  

- if you are taking any of various types of medicines which could cause a change in the rhythm of 
your heartbeat. These include:  

 some types of antiarrhythmics (medicines used to correct irregular heart beats, e.g. 
quinidine, amiodarone, sotalol, dofetilide)  

 medicines to treat psychosis (loss of contact with reality, e.g. thioridazine)  
 medicines for depression (e.g. amitriptyline)  
 some types of medicines to treat bacterial infections (e.g. erythromycin and sparfloxacin) 
 some medicines to treat allergies such as hay fever, called antihistamines (e.g. terfenadine 

and astemizole) 
 any medicines that cause a decrease in magnesium or potassium in your blood (e.g. 

amphotericin B) 
 cisapride (a medicine used to relieve certain stomach problems).  

The effect of these medicines on your heartbeat can be made worse by TRISENOX. You must 
be sure to tell your doctor about all medicines you are taking. 

- if you are taking or have recently taken any medicine which may affect your liver. If you are not 
sure, show the bottle or pack to your doctor. 

 
TRISENOX with food and drink 
There are no restrictions on your food or drink while you are receiving TRISENOX. 
 
Pregnancy 
Ask your doctor or pharmacist for advice before taking any medicine.  
TRISENOX may cause harm to the foetus when used by pregnant women.  
If you are able to become pregnant, you must use effective birth control during treatment with 
TRISENOX.  
If you are pregnant or you become pregnant during the treatment with TRISENOX, you must ask your 
doctor for advice. 
Men should also use effective contraception during treatment with TRISENOX. 
 
Breast-feeding 
Ask your doctor or pharmacist for advice before taking any medicine.  
The arsenic in TRISENOX passes into breast milk.  
Because TRISENOX can harm nursing infants, do not breast-feed while on TRISENOX. 
 
Driving and using machines 
TRISENOX is expected to have no or negligible influence on your ability to drive and use machines. 
If you experience discomfort or if you feel unwell after a TRISENOX injection, you should wait until 
the symptoms go away before driving or using machines. 
 
TRISENOX contains sodium 
TRISENOX contains less than 1 mmol sodium (23 mg) per dose. This means that the medicine is 
essentially ‘sodium-free’. 
 
 
3. How TRISENOX is given 
 
Duration and frequency of treatment 



31 

 
Patients with newly diagnosed acute promyelocytic leukaemia 
Your doctor will give you TRISENOX once every day as an infusion. In your first treatment cycle, 
you may be treated every day up to 60 days at most or until your doctor determines that your disease is 
better. If your disease responds to TRISENOX, you will be given 4 additional treatment cycles. Each 
cycle consists of 20 doses given 5 days per week (followed by 2 days interruption) for 4 weeks 
followed by 4 weeks interruption. Your doctor will decide exactly how long you must continue on 
therapy with TRISENOX. 
 
Patients with acute promyelocytic leukaemia, whose disease has not responded to other therapies 
Your doctor will give you TRISENOX once every day as an infusion. In your first treatment cycle, 
you may be treated every day up to 50 days at most or until your doctor determines that your disease is 
better. If your disease responds to TRISENOX, you will be given a second treatment cycle of 25 doses 
given 5 days per week (followed by 2 days interruption) for 5 weeks. Your doctor will decide exactly 
how long you must continue on therapy with TRISENOX. 
 
Method and route of administration 
 
TRISENOX must be diluted with a solution containing glucose or a solution containing sodium 
chloride. 
 
TRISENOX is normally given by a doctor or a nurse. It is given as a drip (infusion) into a vein over 
1-2 hours, but the infusion may last longer if side effects like flushing and dizziness occur.  
 
TRISENOX must not be mixed with, or infused through the same tube with other medicines.  
 
If your doctor or nurse gives you more TRISENOX than he/she should 
You may experience convulsions, muscle weakness and confusion. If this happens, treatment with 
TRISENOX must be stopped immediately and your doctor will treat the arsenic overdose.  
 
If you have any further question on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor or nurse straight away if you notice the following side effects, as these may be 
signs of a severe condition called “differentiation syndrome”, which might be fatal: 
- difficulty in breathing  
- coughing  
- chest pain  
- fever  
 
Tell your doctor or nurse straight away if you notice one or more of the following side effects, as 
these may be signs of allergic reaction: 
- difficulty in breathing  
- fever  
- sudden weight gain  
- water retention  
- fainting  
- palpitations (strong heartbeat you can feel in your chest) 
 
While on treatment with TRISENOX, you may experience some of the following reactions: 
 
Very common (may affect more than 1 in 10 people): 
- fatigue (weariness), pain, fever, headache 



32 

- nausea, vomiting, diarrhoea 
- dizziness, muscle pain, numbness or tingling 
- rash or itching, increased blood sugar, oedema (swelling due to excess fluid) 
- shortness of breath, fast heart beat, abnormal ECG heart tracing 
- reduced potassium or magnesium in the blood, liver function tests abnormal including presence 

of excess bilirubin or gamma-glutamyltransferase in the blood 
 
Common (may affect up to 1 in 10 people): 
- reduction in blood cell counts (platelets, red and/or white blood cells), increased white blood 

cells 
- chills, increased weight 
- a fever due to an infection and low levels of white blood cells, herpes zoster infection 
- chest pain, bleeding in the lung, hypoxia (low oxygen level), collection of fluid around the heart 

or the lung, low blood pressure, abnormal heart rhythm 
- fit, joint or bone pain, inflammation of the blood vessels 
- increased sodium or magnesium, ketones in the blood and urine (ketoacidosis), renal function 

tests abnormal, kidney failure 
- stomach (abdominal) ache 
- redness of the skin, swollen face, blurred vision  
 
Not known (frequency cannot be estimated from the available data): 
- lung infection, infection in the blood 
- inflammation of the lungs which causes chest pain and breathlessness, cardiac failure 
- dehydration, confusion 
- Cerebral disease (Encephalopathy, Wernicke encephalopathy) with various manifestations 

including difficulties to use arms and legs, speech disorders and confusion 
 
Reporting of side effects  
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.  
 
5. How to store TRISENOX 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the ampoule label and the carton. 
 
This medicine does not require any special storage conditions. 
 
After dilution, if not used immediately, storage times and conditions before use are the responsibility 
of your doctor, pharmacist or nurse and would normally not be longer than 24 hours at 2 to 8 ºC, 
unless dilution has taken place in a sterile environment. 
 
This medicine must not be used if you notice foreign particulate matter or if the solution is 
discoloured. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What TRISENOX contains 
- The active substance is arsenic trioxide. Each ml of concentrate contains 1 mg of arsenic 
trioxide. Each ampoule of 10 ml contains 10 mg of arsenic trioxide. 



33 

- The other ingredients are sodium hydroxide, hydrochloric acid and water for injections. See 
section 2 “TRISENOX contains sodium”. 
 
What TRISENOX looks like and contents of the pack 
- TRISENOX is a concentrate for solution for infusion (sterile concentrate). TRISENOX is 
supplied in glass ampoules as a concentrated, clear, colourless, aqueous solution. Each carton contains 
10 single-use glass ampoules. 
 
Marketing Authorisation Holder 
Teva B.V., Swensweg 5, 2031 GA Haarlem, Netherlands  
 
Manufacturer 
Almac Pharma Services Limited, Almac House, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, 
United Kingdom 
 
Almac Pharma Services (Ireland) Limited; Finnabair Industrial Estate, Dundalk, Co. Louth, 
A91 P9KD, Ireland 
 
Teva Pharmaceuticals Europe B.V., Swensweg 5, 2031 GA Haarlem, The Netherlands 
 
 
This leaflet was last revised in {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu    
There are also links to other websites about rare diseases and treatments. 
 
 
---------------------------------------------------------------------------------------------------------------------------
--- 
 
The following information is intended for medical or healthcare professionals only: 
 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 
TRISENOX SINCE NO PRESERVATIVE IS PRESENT. 
 
Dilution of TRISENOX 
TRISENOX must be diluted before administration.  
Personnel should be trained to handle and dilute arsenic trioxide and should wear appropriate 
protective clothing. 
 
Opening the ampoule: Hold the ampoule of TRISENOX with the coloured point upwards and in front 
of you. Shake or tap the ampoule to get any fluid in the stem into the body of the ampoule. Now press 
your thumb on the coloured point and break the ampoule by holding firmly the body of the ampoule 
with the other hand.  
 
Dilution: Carefully insert the needle of a syringe into the ampoule and draw up all of the content. 
TRISENOX must then be diluted immediately with 100 to 250 ml of glucose 50 mg/ml (5 %) solution 
for injection or sodium chloride 9 mg/ml (0.9 %) solution for injection. 
 
Unused portions of each ampoule must be discarded properly. Do not save any unused portions for 
later administration. 
 
Use of TRISENOX 
TRISENOX is for single use only. It must not be mixed with or concomitantly administered in the 
same intravenous line with other medicinal products.  
 



34 

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. 
 
The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually 
for particulate matter and discoloration prior to administration. Do not use the preparation if foreign 
particulate matter is present.  
 
After dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at 
15-30 °C and 72 hours at refrigerated (2-8 °C) temperatures. From a microbiological point of view, the 
product must be used immediately. If not used immediately, in-use storage times and conditions prior 
to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 °C, 
unless dilution has taken place in controlled and validated aseptic conditions. 
 
Procedure for proper disposal 
Any unused product, any items that come into contact with the product and waste material must be 
disposed of in accordance with local requirements. 
 



35 

Package leaflet: Information for the patient 
 

TRISENOX 2 mg/ml concentrate for solution for infusion 
arsenic trioxide 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have further questions, please ask your doctor, pharmacist or nurse. 
-- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
 
1. What TRISENOX is and what it is used for 
2. What you need to know before you are given TRISENOX 
3. How TRISENOX is given 
4. Possible side effects 
5. How to store TRISENOX 
6. Contents of the pack and other information 
 
 
1. What TRISENOX is and what it is used for 
 
TRISENOX is used in adult patients with newly diagnosed low-to-intermediate risk acute 
promyelocytic leukaemia (APL), and in adult patients, whose disease has not responded to other 
therapies. APL is a unique type of myeloid leukaemia, a disease in which abnormal white blood cells 
and abnormal bleeding and bruising occur. 
 
 
2. What you need to know before you are given TRISENOX 
 
TRISENOX must be given under the supervision of a physician experienced in the treatment of acute 
leukaemias.  
 
You must not receive TRISENOX 
If you are allergic to arsenic trioxide or any of the other ingredients of this medicine (listed in 
section 6). 
 
Warnings and precautions 
You must talk to your doctor or nurse before you are given TRISENOX, if 

- you have impaired kidney function. 
- you have any liver problems. 

 
Your doctor will take the following precautions: 

- Tests will be performed to check the amount of potassium, magnesium, calcium and creatinine 
in your blood before your first dose of TRISENOX.  

- You should have an electrical recording of the heart (electrocardiogram ECG) performed before 
your first dose.  

- Blood tests (potassium, calcium, magnesium and liver function) should be repeated during your 
treatment with TRISENOX.  

- In addition, you will receive electrocardiograms twice weekly.  
- If you are at risk for a certain type of abnormal heart rhythm (e.g. torsade de pointes or QTc 

prolongation), your heart will be monitored continuously.  
- Your doctor may monitor your health during and after treatment, since arsenic trioxide, the 

active substance in TRISENOX, may cause other cancers. You should report any new and 
exceptional symptoms and circumstances whenever you see your doctor.  



36 

- Follow-up of your cognitive and mobility functions if you are at risk for vitamin B1 deficiency. 
 
Children and adolescents 
TRISENOX is not recommended in children and adolescents below 18 years of age. 
 
Other medicines and TRISENOX 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 
In particular tell your doctor  

- if you are taking any of various types of medicines which could cause a change in the rhythm of 
your heartbeat. These include:  

 some types of antiarrhythmics (medicines used to correct irregular heart beats, e.g. 
quinidine, amiodarone, sotalol, dofetilide)  

 medicines to treat psychosis (loss of contact with reality, e.g. thioridazine)  
 medicines for depression (e.g. amitriptyline)  
 some types of medicines to treat bacterial infections (e.g. erythromycin and sparfloxacin) 
 some medicines to treat allergies such as hay fever, called antihistamines (e.g. terfenadine 

and astemizole) 
 any medicines that cause a decrease in magnesium or potassium in your blood (e.g. 

amphotericin B)  
 cisapride (a medicine used to relieve certain stomach problems).  

The effect of these medicines on your heartbeat can be made worse by TRISENOX. You must 
be sure to tell your doctor about all medicines you are taking. 

- if you are taking or have recently taken any medicine which may affect your liver. If you are not 
sure, show the bottle or pack to your doctor. 

 
TRISENOX with food and drink 
There are no restrictions on your food or drink while you are receiving TRISENOX. 
 
Pregnancy 
Ask your doctor or pharmacist for advice before taking any medicine.  
TRISENOX may cause harm to the foetus when used by pregnant women.  
If you are able to become pregnant, you must use effective birth control during treatment with 
TRISENOX.  
If you are pregnant or you become pregnant during the treatment with TRISENOX, you must ask your 
doctor for advice. 
Men should also use effective contraception during treatment with TRISENOX. 
 
Breast-feeding 
Ask your doctor or pharmacist for advice before taking any medicine.  
The arsenic in TRISENOX passes into breast milk.  
Because TRISENOX can harm nursing infants, do not breast-feed while on TRISENOX. 
 
Driving and using machines 
TRISENOX is expected to have no or negligible influence on your ability to drive and use machines. 
If you experience discomfort or if you feel unwell after a TRISENOX injection, you should wait until 
the symptoms go away before driving or using machines. 
 
TRISENOX contains sodium 
TRISENOX contains less than 1 mmol sodium (23 mg) per dose. This means that the medicine is 
essentially ‘sodium-free’. 
 
 
3. How TRISENOX is given 
 
Duration and frequency of treatment 



37 

 
Patients with newly diagnosed acute promyelocytic leukaemia 
Your doctor will give you TRISENOX once every day as an infusion. In your first treatment cycle, 
you may be treated every day up to 60 days at most or until your doctor determines that your disease is 
better. If your disease responds to TRISENOX, you will be given 4 additional treatment cycles. Each 
cycle consists of 20 doses given 5 days per week (followed by 2 days interruption) for 4 weeks 
followed by 4 weeks interruption. Your doctor will decide exactly how long you must continue on 
therapy with TRISENOX. 
 
Patients with acute promyelocytic leukaemia, whose disease has not responded to other therapies 
Your doctor will give you TRISENOX once every day as an infusion. In your first treatment cycle, 
you may be treated every day up to 50 days at most or until your doctor determines that your disease is 
better. If your disease responds to TRISENOX, you will be given a second treatment cycle of 25 doses 
given 5 days per week (followed by 2 days interruption) for 5 weeks. Your doctor will decide exactly 
how long you must continue on therapy with TRISENOX. 
 
Method and route of administration 
 
TRISENOX must be diluted with a solution containing glucose or a solution containing sodium 
chloride. 
 
TRISENOX is normally given by a doctor or a nurse. It is given as a drip (infusion) into a vein over 
1-2 hours, but the infusion may last longer if side effects like flushing and dizziness occur.  
 
TRISENOX must not be mixed with, or infused through the same tube with other medicines.  
 
If your doctor or nurse gives you more TRISENOX than he/she should 
You may experience convulsions, muscle weakness and confusion. If this happens, treatment with 
TRISENOX must be stopped immediately and your doctor will treat the arsenic overdose.  
 
If you have any further question on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor or nurse straight away if you notice the following side effects, as these may be 
signs of a severe condition called “differentiation syndrome”, which might be fatal: 
- difficulty in breathing  
- coughing  
- chest pain  
- fever  
 
Tell your doctor or nurse straight away if you notice one or more of the following side effects, as 
these may be signs of allergic reaction: 
- difficulty in breathing  
- fever  
- sudden weight gain  
- water retention  
- fainting  
- palpitations (strong heartbeat you can feel in your chest) 
 
While on treatment with TRISENOX, you may experience some of the following reactions: 
 
Very common (may affect more than 1 in 10 people): 
- fatigue (weariness), pain, fever, headache 



38 

- nausea, vomiting, diarrhoea 
- dizziness, muscle pain, numbness or tingling 
- rash or itching, increased blood sugar, oedema (swelling due to excess fluid) 
- shortness of breath, fast heart beat, abnormal ECG heart tracing 
- reduced potassium or magnesium in the blood, liver function tests abnormal including presence 

of excess bilirubin or gamma-glutamyltransferase in the blood 
 
Common (may affect up to 1 in 10 people): 
- reduction in blood cell counts (platelets, red and/or white blood cells), increased white blood 

cells 
- chills, increased weight 
- a fever due to an infection and low levels of white blood cells, herpes zoster infection 
- chest pain, bleeding in the lung, hypoxia (low oxygen level), collection of fluid around the heart 

or the lung, low blood pressure, abnormal heart rhythm 
- fit, joint or bone pain, inflammation of the blood vessels 
- increased sodium or magnesium, ketones in the blood and urine (ketoacidosis), renal function 

tests abnormal, kidney failure 
- stomach (abdominal) ache 
- redness of the skin, swollen face, blurred vision  
 
Not known (frequency cannot be estimated from the available data): 
- lung infection, infection in the blood 
- inflammation of the lungs which causes chest pain and breathlessness, cardiac failure 
- dehydration, confusion 
- Cerebral disease (Encephalopathy, Wernicke encephalopathy) with various manifestations 

including difficulties to use arms and legs, speech disorders and confusion 
 
Reporting of side effects  
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.  
 
5. How to store TRISENOX 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial label and the carton. 
 
This medicine does not require any special storage conditions. 
 
After dilution, if not used immediately, storage times and conditions before use are the responsibility 
of your doctor, pharmacist or nurse and would normally not be longer than 24 hours at 2 to 8 ºC, 
unless dilution has taken place in a sterile environment. 
 
This medicine must not be used if you notice foreign particulate matter or if the solution is 
discoloured. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What TRISENOX contains 
- The active substance is arsenic trioxide. Each ml of concentrate contains 2 mg of arsenic 

trioxide. Each vial of 6 ml contains 12 mg of arsenic trioxide. 



39 

- The other ingredients are sodium hydroxide, hydrochloric acid and water for injections. See 
section 2 “TRISENOX contains sodium”. 

 
What TRISENOX looks like and contents of the pack 
- TRISENOX is a concentrate for solution for infusion (sterile concentrate). TRISENOX is 

supplied in glass vials as a concentrated, clear, colourless, aqueous solution. Each carton 
contains 10 single-use glass vials.  

 
Marketing Authorisation Holder 
Teva B.V., Swensweg 5, 2031 GA Haarlem, Netherlands  
 
Manufacturer 
Teva Pharmaceuticals Europe B.V., Swensweg 5, 2031 GA Haarlem, The Netherlands 
 
 
This leaflet was last revised in {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
There are also links to other websites about rare diseases and treatments. 
 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for medical or healthcare professionals only: 
 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 
TRISENOX SINCE NO PRESERVATIVE IS PRESENT. 
 
Dilution of TRISENOX 
TRISENOX must be diluted before administration.  
Personnel should be trained to handle and dilute arsenic trioxide and should wear appropriate 
protective clothing. 
 
 
 
Dilution: Carefully insert the needle of a syringe into the vial and withdraw the required volume. 
TRISENOX must then be diluted immediately with 100 to 250 ml of glucose 50 mg/ml (5 %) solution 
for injection or sodium chloride 9 mg/ml (0.9 %) solution for injection. 
 
Unused portions of each vial must be discarded properly. Do not save any unused portions for later 
administration. 
 
Use of TRISENOX 
TRISENOX is for single use only. It must not be mixed with or concomitantly administered in the 
same intravenous line with other medicinal products.  
 
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. 
 
The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually 
for particulate matter and discoloration prior to administration. Do not use the preparation if foreign 
particulate matter is present.  
 
After dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at 
15-30 °C and 72 hours at refrigerated (2-8 °C) temperatures. From a microbiological point of view, the 
product must be used immediately. If not used immediately, in-use storage times and conditions prior 

CAUTION, NOTICE NEW CONCENTRATION (2 mg/ml) 



40 

to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 °C, 
unless dilution has taken place in controlled and validated aseptic conditions. 
 
Procedure for proper disposal 
Any unused product, any items that come into contact with the product and waste material must be 
disposed of in accordance with local requirements. 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVEUSE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you are given trisenox', 'Section_Content': "trisenox must be given under the supervision of a physician experienced in the treatment of acute leukaemias. you must not receive trisenox if you are allergic to arsenic trioxide or any of the other ingredients of this medicine (listed in section 6). warnings and precautions you must talk to your doctor or nurse before you are given trisenox, if - you have impaired kidney function. - you have any liver problems. your doctor will take the following precautions: - tests will be performed to check the amount of potassium, magnesium, calcium and creatinine in your blood before your first dose of trisenox. - you should have an electrical recording of the heart (electrocardiogram ecg) performed before your first dose. - blood tests (potassium, calcium, magnesium and liver function) should be repeated during your treatment with trisenox. - in addition, you will receive electrocardiograms twice weekly. - if you are at risk for a certain type of abnormal heart rhythm (e.g. torsade de pointes or qtc prolongation), your heart will be monitored continuously. - your doctor may monitor your health during and after treatment, since arsenic trioxide, the active substance in trisenox, may cause other cancers. you should report any new and exceptional symptoms and circumstances whenever you see your doctor. - follow-up of your cognitive and mobility functions if you are at risk for vitamin b1 deficiency. children and adolescents trisenox is not recommended in children and adolescents below 18 years of age. other medicines and trisenox tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. in particular tell your doctor - if you are taking any of various types of medicines which could cause a change in the rhythm of your heartbeat. these include: some types of antiarrhythmics (medicines used to correct irregular heart beats, e.g. quinidine, amiodarone, sotalol, dofetilide) medicines to treat psychosis (loss of contact with reality, e.g. thioridazine) medicines for depression (e.g. amitriptyline) some types of medicines to treat bacterial infections (e.g. erythromycin and sparfloxacin) some medicines to treat allergies such as hay fever, called antihistamines (e.g. terfenadine and astemizole) any medicines that cause a decrease in magnesium or potassium in your blood (e.g. amphotericin b) cisapride (a medicine used to relieve certain stomach problems). the effect of these medicines on your heartbeat can be made worse by trisenox. you must be sure to tell your doctor about all medicines you are taking. - if you are taking or have recently taken any medicine which may affect your liver. if you are not sure, show the bottle or pack to your doctor. trisenox with food and drink there are no restrictions on your food or drink while you are receiving trisenox. pregnancy ask your doctor or pharmacist for advice before taking any medicine. trisenox may cause harm to the foetus when used by pregnant women. if you are able to become pregnant, you must use effective birth control during treatment with trisenox. if you are pregnant or you become pregnant during the treatment with trisenox, you must ask your doctor for advice. men should also use effective contraception during treatment with trisenox. breast-feeding ask your doctor or pharmacist for advice before taking any medicine. the arsenic in trisenox passes into breast milk. because trisenox can harm nursing infants, do not breast-feed while on trisenox. driving and using machines trisenox is expected to have no or negligible influence on your ability to drive and use machines. if you experience discomfort or if you feel unwell after a trisenox injection, you should wait until the symptoms go away before driving or using machines. trisenox contains sodium trisenox contains less than 1 mmol sodium (23 mg) per 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{'Title': '3. how trisenox is given', 'Section_Content': 'duration and frequency of treatment 31 patients with newly diagnosed acute promyelocytic leukaemia your doctor will give you trisenox once every day as an infusion. in your first treatment cycle, you may be treated every day up to 60 days at most or until your doctor determines that your disease is better. if your disease responds to trisenox, you will be given 4 additional treatment cycles. each cycle consists of 20 doses given 5 days per week (followed by 2 days interruption) for 4 weeks followed by 4 weeks interruption. your doctor will decide exactly how long you must continue on therapy with trisenox. patients with acute promyelocytic leukaemia, whose disease has not responded to other therapies your doctor will give you trisenox once every day as an infusion. in your first treatment cycle, you may be treated every day up to 50 days at most or until your doctor determines that your disease is better. if your disease responds to trisenox, you will be given a second treatment cycle of 25 doses given 5 days per week (followed by 2 days interruption) for 5 weeks. your doctor will decide exactly how long you must continue on therapy with trisenox. method and route of administration trisenox must be diluted with a solution containing glucose or a solution containing sodium chloride. trisenox is normally given by a doctor or a nurse. it is given as a drip (infusion) into a vein over 1-2 hours, but the infusion may last longer if side effects like flushing and dizziness occur. trisenox must not be mixed with, or infused through the same tube with other medicines. if your doctor or nurse gives you more trisenox than he/she should you may experience convulsions, muscle weakness and confusion. if this happens, treatment with trisenox must be stopped immediately and your doctor will treat the arsenic overdose. if you have any further question on the use of this medicine, ask your doctor, pharmacist or 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or nurse straight away if you notice the following side effects, as these may be signs of a severe condition called "differentiation syndrome", which might be fatal: - difficulty in breathing - coughing - chest pain - fever tell your doctor or nurse straight away if you notice one or more of the following side effects, as these may be signs of allergic reaction: - difficulty in breathing - fever - sudden weight gain - water retention - fainting - palpitations (strong heartbeat you can feel in your chest) while on treatment with trisenox, you may experience some of the following reactions: very common (may affect more than 1 in 10 people): - fatigue (weariness), pain, fever, headache 32 - nausea, vomiting, diarrhoea - dizziness, muscle pain, numbness or tingling - rash or itching, increased blood sugar, oedema (swelling due to excess fluid) - shortness of breath, fast heart beat, abnormal ecg heart tracing - reduced potassium or magnesium in the blood, liver function tests abnormal including presence of excess bilirubin or gamma-glutamyltransferase in the blood common (may affect up to 1 in 10 people): - reduction in blood cell counts (platelets, red and/or white blood cells), increased white blood cells - chills, increased weight - a fever due to an infection and low levels of white blood cells, herpes zoster infection - chest pain, bleeding in the lung, hypoxia (low oxygen level), collection of fluid around the heart or the lung, low blood pressure, abnormal heart rhythm - fit, joint or bone pain, inflammation of the blood vessels - increased sodium or magnesium, ketones in the blood and urine (ketoacidosis), renal function tests abnormal, kidney failure - stomach (abdominal) ache - redness of the skin, swollen face, blurred vision not known (frequency cannot be estimated from the available data): - lung infection, infection in the blood - inflammation of the lungs which causes chest pain and breathlessness, cardiac failure - dehydration, confusion - cerebral disease (encephalopathy, wernicke encephalopathy) with various manifestations including difficulties to use arms and legs, speech disorders and confusion reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'trisenox', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 20, 'BeginOffset': 44, 'EndOffset': 56, 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{'Title': '5. how to store trisenox', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the ampoule label and the carton. this medicine does not require any special storage conditions. after dilution, if not used immediately, storage times and conditions before use are the responsibility of your doctor, pharmacist or nurse and would normally not be longer than 24 hours at 2 to 8 ºc, unless dilution has taken place in a sterile environment. this medicine must not be used if you notice foreign particulate matter or if the solution is discoloured. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'trisenox', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 400, 'EndOffset': 402}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 412, 'EndOffset': 413}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 417, 'EndOffset': 418}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 481, 'EndOffset': 494}, {'Text': 'foreign particulate matter', 'Type': 'PROBLEM', 'BeginOffset': 526, 'EndOffset': 552}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 722, 'EndOffset': 736}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what trisenox contains - the active substance is arsenic trioxide. each ml of concentrate contains 1 mg of arsenic trioxide. each ampoule of 10 ml contains 10 mg of arsenic trioxide. - the other ingredients are sodium hydroxide, hydrochloric acid and water for injections. see section 2 "trisenox contains sodium". what trisenox looks like and contents of the pack - trisenox is a concentrate for solution for infusion (sterile concentrate). trisenox is supplied in glass ampoules as a concentrated, clear, colourless, aqueous solution. each carton contains 10 single-use glass ampoules.', 'Entity_Recognition': [{'Text': 'trisenox', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 65, 'Score': 0.9557314515113831, 'Text': 'arsenic trioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 78, 'EndOffset': 98, 'Score': 0.8154585957527161, 'Text': 'concentrate contains', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.4301018714904785, 'RelationshipScore': 0.9999934434890747, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 67, 'EndOffset': 74, 'Text': 'each ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 99, 'EndOffset': 100}, {'Id': 4, 'BeginOffset': 107, 'EndOffset': 123, 'Score': 0.9711069464683533, 'Text': 'arsenic trioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.939245879650116, 'RelationshipScore': 0.9999080896377563, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 99, 'EndOffset': 103, 'Text': '1 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9867244362831116, 'RelationshipScore': 0.962466835975647, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 141, 'EndOffset': 146, 'Text': '10 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 141, 'EndOffset': 143}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 156, 'EndOffset': 158}, {'Id': 7, 'BeginOffset': 165, 'EndOffset': 181, 'Score': 0.9713079929351807, 'Text': 'arsenic trioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.939245879650116, 'RelationshipScore': 0.8781176805496216, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 99, 'EndOffset': 103, 'Text': '1 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9867244362831116, 'RelationshipScore': 0.7505425810813904, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 141, 'EndOffset': 146, 'Text': '10 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9631628394126892, 'RelationshipScore': 0.9999927282333374, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 156, 'EndOffset': 161, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 8, 'BeginOffset': 211, 'EndOffset': 227, 'Score': 0.9950124621391296, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9631628394126892, 'RelationshipScore': 0.5733282566070557, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 156, 'EndOffset': 161, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 9, 'BeginOffset': 229, 'EndOffset': 246, 'Score': 0.9936929941177368, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 261, 'EndOffset': 271}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 285, 'EndOffset': 286}, {'Id': 10, 'BeginOffset': 288, 'EndOffset': 296, 'Score': 0.4856281280517578, 'Text': 'trisenox', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 306, 'EndOffset': 312, 'Score': 0.4455343782901764, 'Text': 'sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 320, 'EndOffset': 328, 'Score': 0.4771665632724762, 'Text': 'trisenox', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the pack - trisenox', 'Type': 'TREATMENT', 'BeginOffset': 356, 'EndOffset': 375}, {'Text': 'infusion (sterile concentrate', 'Type': 'TREATMENT', 'BeginOffset': 410, 'EndOffset': 439}, {'Id': 15, 'BeginOffset': 442, 'EndOffset': 450, 'Score': 0.6998277306556702, 'Text': 'trisenox', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 558, 'EndOffset': 560}, {'Text': 'glass ampoules', 'Type': 'TREATMENT', 'BeginOffset': 572, 'EndOffset': 586}]}