Arsenic trioxide Accord

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 

Arsenic trioxide Accord 1 mg/ml concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

One ml of  concentrate for solution for infusion contains 1 mg of arsenic trioxide.  

One vial of 10 ml contains 10 mg of arsenic trioxide.  
 

For the full list of excipients, see section 6.1 

 

3. PHARMACEUTICAL FORM 
 

Concentrate for solution for infusion  

Sterile, clear, colourless, aqueous solution, free from particles having a pH range of 7.7 – 8.3. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Arsenic trioxide 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 
 

Arsenic trioxide must be administered under the supervision of a physician who is experienced in the 

management of acute leukaemias, and the special monitoring procedures described in section 4.4 must 

be followed. 

 

Posology 

 

The same dose is recommended for adults and elderly. 

 

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

 

Induction treatment schedule 

Arsenic trioxide 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 

Arsenic trioxide 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) 



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Induction treatment schedule 

Arsenic trioxide 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. Arsenic 

trioxide 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 arsenic trioxide 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 Arsenic trioxide treatment. Patients who 

experience such reactions that are considered arsenic trioxide 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 

Patients with 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 Arsenic trioxide in 

patients with hepatic impairment (see section 4.4 and 4.8). 

 

Patients with renal impairment 

 

Since no data are available across all renal impairment groups, caution is advised in the use of Arsenic 

trioxide in patients with renal impairment. 

 

Paediatric population 

 

The safety and efficacy of Arsenic trioxide 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 

 

Arsenic trioxide must be administered intravenously over 1-2 hours. The infusion duration may be 

extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required. 

Patients must be hospitalised at the beginning of treatment due to symptoms of disease and to ensure 

adequate monitoring. 

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

 



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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 leukocytosis. This 

syndrome can be fatal. In newly diagnosed APL patients treated with arsenic trioxide and 

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 arsenic trioxide 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 arsenic trioxide therapy during treatment of the APL differentiation 

syndrome. As soon as signs and symptoms have subsided, treatment with arsenic trioxide can be 

resumed at 50 % of the previous dose during the first 7 days. Thereafter, in the absence of worsening 

of the previous toxicity, arsenic trioxide might be resumed at full dosage. In the case of the 

reappearance of symptoms arsenic trioxide 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 

arsenic trioxide 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 arsenic trioxide. 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 hypokalemia or hypomagnesaemia. In clinical trials, in the relapsed/refractory setting, 40% 

of patients treated with arsenic trioxide 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 arsenic trioxide infusion, and then returned to baseline by the end of 8 weeks after arsenic 

trioxide infusion. One patient (receiving multiple, concomitant medicinal products, including 

amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL 

with arsenic trioxide. In newly diagnosed APL patients 15.6 % showed QTc prolongation with 

arsenic trioxide in combination with ATRA (see section 4.8). In one newly diagnosed patient 



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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 arsenic trioxide, a 12-lead ECG must be performed and serum 

electrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; preexisting 

electrolyte abnormalities must be corrected and, if possible, medicinal products that are known to 

prolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or risk 

factors of Torsade de pointes should be monitored with continuous cardiac monitoring (ECG). For 

QTc greater than 500 msec, corrective measures must be completed and the QTc reassessed with serial 

ECGs and, if available, a specialist advice could be sought prior to considering using arsenic trioxide. 

During therapy with arsenic trioxide, 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 arsenic trioxide therapy must be 

considered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and 

monitored continuously, serum electrolytes must be assessed, arsenic trioxide 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 arsenic trioxide 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 arsenic trioxide 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 arsenic 

trioxide should be resumed at 50 % of the previous dose during the first 7 days. Thereafter, in 

absence of worsening of the previous toxicity, arsenic trioxide should be resumed at full dosage. In 

case of reappearance of hepatotoxicity, arsenic trioxide must be permanently discontinued. 

 

Dose delay and modification 

Treatment with arsenic trioxide 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 arsenic trioxide 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. 

 

Patients with renal impairment 

Since no data are available across all renal impairment groups, caution is advised in the use of 

arsenic trioxide 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 arsenic trioxide in patients on dialysis has not been studied. 

 

Patients with hepatic impairment 

Since no data are available across all hepatic impairment groups and hepatotoxic effects may occur 



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during the treatment with arsenic trioxide caution is advised in the use of arsenic trioxide 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 arsenic trioxide in the elderly population. Caution is needed 

in these patients. 

 

Hyperleukocytosis 
Treatment with arsenic trioxide has been associated with the development of hyperleukocytosis  
(≥ 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 
hyperleukocytosis nor did there appear to be a correlation between baseline WBC count and peak 
WBC counts. Hyperleukocytosis was never treated with additional chemotherapy and resolved 
on continuation of arsenic trioxide. 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 
leukocytosis; however, in all these patients, the WBC count was declining or had normalized by 
the time of bone marrow remission and cytotoxic chemotherapy or leukopheresis was not 
required. In newly diagnosed patients with low to intermediate risk APL leukocytosis 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 leukocytosis 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 10
3

/µl  500 mg four times a day 

 > 50 x 10
3

/µl  1000 mg four times a day 

 

Development of second primary malignancies 

The active ingredient of Arsenic trioxide Accord, arsenic trioxide, is a human carcinogen. Monitor 

patients for the development of second primary malignancies. 

 

Arsenic trioxide Accord contains sodium: 

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 arsenic trioxide and other therapeutic 

medicinal products have been conducted. 

 

Medicinal products known to cause QT/QTc interval prolongation, hypokalemia 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 hypokalemia or hypomagnesaemia, such as diuretics or amphotericin B, may 

be at higher risk for torsade de pointes. Caution is advised when arsenic trioxide is coadministered 

with other medicinal products known to cause QT/QTc interval prolongation such as macrolide 

antibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalemia or 

hypomagnesaemia. Additional information about QT prolonging medicinal agents is provided in 

Section 4.4. 

 



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Medicinal products known to cause hepatotoxic effects 

 

Hepatotoxic effects may occur during the treatment with arsenic trioxide, caution is advised when 

arsenic trioxide is coadministered with other medicinal products known to cause hepatotoxic effects 

(see section 4.4 and 4.8). 

 

Other antileukaemic medicinal products 

 

The influence of arsenic trioxide 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 

arsenic trioxide. 

 

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 arsenic trioxide. 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 from arsenic trioxide, breast-feeding must be discontinued prior to and throughout 

administration. 

 

Fertility 

 

No clinical or non-clinical fertility studies have been conducted with arsenic trioxide. 

 

4.7 Effects on ability to drive and use machines 
 

Arsenic trioxide 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). Leukocytosis 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), leukocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrial 

fibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related to 

haemorrhage, infections, pain, diarrhoea, nausea. 

 

In general, 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 



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tended to tolerate consolidation and maintenance treatment with less toxicity than in induction. This 

is probably due to the confounding of adverse events by the uncontrolled disease process early on in 

the treatment course and the myriad concomitant medicinal products required to control symptoms 

and morbidity. 

 

In a phase 3, multicenter, noninferiority 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 arsenic trioxide 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 

Leukocytosis 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 



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 All grades Grades ≥ 3 

Convulsion Common Not known 

Eye disorders   

Vision blurred Common Not known 

Cardiac disorders   

Tachycardia Very common Common 

Pericardial effusion Common Common 

Ventricular extrasystoles Common Not known 

Cardiac failure Not known Not known 

Ventricular tachycardia Not known Not known 

Vascular disorders   

Vasculitis Common Common 

Hypotension Common Not known 

Respiratory, thoracic and mediastinal disorders 

Differentiation syndrome Very common Very common 

Dyspnoea Very common Common 

Hypoxia Common Common 

Pleural effusion Common Common 

Pleuritic pain Common Common 

Pulmonary alveolar 

haemorrhage 

Common Common 

Pneumonitis Not known Not known 

Gastrointestinal disorders   

Diarrhoea Very common Common 

Vomiting Very common Not known 

Nausea Very common Not known 

Abdominal pain Common Common 

Skin and subcutaneous tissue disorders 

Pruritus Very common Not known 

Rash Very common Not known 

Erythema Common Common 

Face oedema Common Not known 

Musculoskeletal and connective tissue disorders 

Myalgia Very common Common 

Arthralgia Common Common 

Bone pain Common Common 

Renal and urinary disorders   

Renal failure Common Not known 

General disorders and administration site conditions 

Pyrexia Very common Common 

Pain Very common Common 

Fatigue Very common Not known 

Oedema Very common Not known 

Chest pain Common Common 

Chills Common Not known 

Investigations   

Alanine amino transferase 

increased 

Very common Common 

Aspartate amino transferase 

increased 

Very common Common 

Electrocardiogram QT 

prolonged 

Very common Common 

Hyperbilirubinaemia Common Common 



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 All grades Grades ≥ 3 

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 arsenic trioxide consolidation cycles (cycle 1 and cycle 2) versus 

none in the control arm. 

 

Description of selected adverse reactions 

 

Differentiation syndrome 

During arsenic trioxide 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 leukocytosis (see 

section 4.4). Twenty-seven patients had leukocytosis (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 leukocytosis on study, and WBC counts during consolidation therapy were not as 

high as during induction. In these studies, leukocytosis was not treated with chemotherapeutic 

medicinal products. Medicinal products that are used to lower the white blood cell count often 

exacerbate the toxicities associated with leukocytosis, and no standard approach has proven effective. 

One patient treated under a compassionate use program died from cerebral infarct due to 

leukocytosis, following treatment with chemotherapeutic medicinal products to lower WBC count. 

Observation is the recommended approach with intervention only in selected cases. 

 

Mortality in the pivotal studies 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 authorisation experience, a differentiation syndrome, like retinoic acid syndrome, has also 

been reported for the treatment of malignancies other than APL with arsenic trioxide. 

 

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, preexisting QT interval prolongation, congestive heart 

failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemia 

or hypomagnesaemia. One patient (receiving multiple, concomitant medicinal products, including 

amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL 

with arsenic trioxide. She went onto consolidation without further evidence of QT prolongation. 

 

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 paresthesia/dysesthesia, 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 arsenic trioxide on a subsequent protocol. 

44% 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 



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arsenic trioxide. 

 

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 arsenic trioxide in combination 

with ATRA. However, toxic effects resolved with temporary discontinuation of either arsenic 

trioxide, ATRA or both (see section 4.4). 

 

Haematological and gastrointestinal toxicity 

In newly diagnosed patients with low to intermediate risk APL, gastrointestinal toxicity, grade 3-4 

neutropenia and grade 3 or 4 thrombocytopenia occurred, however these were 2.2 times less frequent 

in patients treated with arsenic trioxide 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, arsenic trioxide must be immediately discontinued and chelating therapy with 

penicillamine at a daily dose ≤ 1 gm 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 gm 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 arsenic trioxide 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 PML/RAR alpha. 

 

Clinical efficacy and safety 

 

Newly diagnosed non high risk APL patients 

 

Arsenic trioxide 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 arsenic trioxide 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-RAR alpha by RT-PCR or micro 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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speckled PML nuclear distribution in leukemic cells were included. No data are available on patient 

with variant translocations like t(11;17) (PLZF/RAR alpha). 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+ arsenic trioxide treatment 

group received oral ATRA at 45 mg/m2 daily and iv arsenic trioxide 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 arsenic trioxide was given at the same dose 5 days per week, 4 weeks on 

and 4 weeks off, for a total of 4 courses. Patients in the ATRA+chemotherapy treatment group 

received iv idarubicin at 12 mg/m2 on days 2, 4, 6, and 8 and oral ATRA at 45 mg/m2 daily until 

CR. During consolidation, patients received idarubicin at 5 mg/m2 on days 1 to 4 and ATRA at 45 

mg/m2 daily for 15 days, then iv mitoxantrone at 10 mg/m2 on days 1 to 5 and ATRA again at 45 

mg/m2  daily for 15 days, and finally a single dose of idarubicin at 12 mg/m2 and ATRA at 45 

mg/m2 daily for 15 days. Each course of consolidation was initiated at hematological 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 +  

Arsenic 

trioxide 

(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 noninferiority 

 

p = 0.02 

for superiority of 

ATRA+Arsenic 

trioxide 

Hematologic 

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 leukemia; ATRA = all-trans-retinoic acid 

 

Relapsed/refractory APL 

 

Arsenic trioxide 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 arsenic trioxide (range 0.06 



13 

 

to 0.20 mg/kg/day) and patients in the multicentre study received a fixed dose of 0.15 mg/kg/day. 

Arsenic trioxide 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 arsenic trioxide for 25 additional doses over a 5 weeks 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. 

 

Table 4 

 Single centre trial 

N=12 

Multicentre trial 

N=40 

Arsenic trioxide 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 arsenic trioxide. Three patients 

from the single institution study and 15 patients from the multicentre study had stem cell transplants 

after completing arsenic trioxide. 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. 

 



14 

 

 
 

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. 

 

Cytogenetics after arsenic trioxide 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 arsenic trioxide 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 less than 18 years of age (range 5 to 16 years) 

treated with arsenic trioxide 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 



15 

 

The volume of distribution (Vd) for As
III 

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 arsenic trioxide. 

 
Elimination 
Approximately 15% of the administered arsenic trioxide 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 



16 

 

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 arsenic 

trioxide. 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, concentrated (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. 

 

6.3 Shelf life 
 

Unopened vial 

2 years 

 

After first opening 

Once opened the product should be used immediately. 

 

After dilution 

Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C and 48 hours at 

2°C to 8°C. 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°C-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 or first opening of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 
 

Type I transparent colorless glass vial sealed with a silicon-oil free, elastomer type, grey rubber 

stopper made of bromobutyl and aluminium seal with a plastic flip off cap containing 10 ml of 

concentrate.  

Each pack contains 1, 5 or 10 vials. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 
 

Preparation of Arsenic trioxide Accord 

 

Aseptic technique must be strictly observed throughout handling of Arsenic trioxide Accord since no 



17 

 

preservative is present. 

 

Arsenic trioxide Accord 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 vial. PVC free plastic bags should be used. It is for single use only, and any unused portions of 

each vial must be discarded properly. Do not save any unused portions for later administration. 

 

Arsenic trioxide Accord must not be mixed with or concomitantly administered in the same 

intravenous line with other medicinal products. 

 

Arsenic trioxide Accord 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. 

 

Procedure for proper disposal 

 

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. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Accord Healthcare S.L.U. 

World Trade Center, Moll de Barcelona S/N,  

Edifici Est, 6a planta,  

08039 Barcelona, 

Spain 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  
 

EU/1/19/1398/001 (pack of 1 vial) 

EU/1/19/1398/002 (pack of 5 vials) 

EU/1/19/1398/003 (pack of 10 vials)  

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 14th November 2019 

 

 

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(s) responsible for batch release 

 

Accord Healthcare Polska Sp. z o.o. 

ul. Lutomierska 50 

95-200 Pabianice 

POLAND 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

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 

 

Arsenic trioxide Accord 1 mg/ml concentrate for solution for infusion  

arsenic trioxide 

 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One ml contains 1 mg of arsenic trioxide. 

 

 

3. LIST OF EXCIPIENTS 

 

Sodium hydroxide 

Hydrochloric acid, concentrated (for pH adjustment)  

Water for injections 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

1 vial of 10 ml (10 mg/10 ml) 

5 vials of 10 ml (10 mg/10 ml) 

10 vials of 10 ml (10 mg/10 ml) 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Intravenous use. Must be diluted before use.  

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 

 

 

 

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 

 

Accord Healthcare S.L.U. 

World Trade Center, Moll de Barcelona S/N,  

Edifici Est, 6a planta,  

08039 Barcelona, 

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/19/1398/001 (pack of 1 vial) 

EU/1/19/1398/002 (pack of 5 vials) 

EU/1/19/1398/003 (pack of 10 vials)  

 

 

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 

 

VIAL  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Arsenic trioxide Accord 1 mg/ml concentrate for solution for infusion  

arsenic trioxide 

IV use after dilution 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

10 mg/10 ml 

 

 

6. OTHER 

 

Cytotoxic 

 



25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



26 

 

Package leaflet: Information for the user 

 

Arsenic trioxide Accord 1 mg/ml concentrate for solution for infusion 

arsenic trioxide 

 

Read all of this leaflet carefully before you start using 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 or your pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist or nurse. This includes 
any possible side effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 
1. What Arsenic trioxide Accord is and what it is used for 
2. What you need to know before you use Arsenic trioxide Accord 
3. How to use Arsenic trioxide Accord 
4. Possible side effects 
5. How to store Arsenic trioxide Accord 
6. Contents of the pack and other information 
 

 

1. What Arsenic trioxide Accord is and what it is used for 
 

Arsenic trioxide Accord contains arsenic trioxide which is an anticancer medicine. It 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 use Arsenic trioxide Accord 
 

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 

including medicines obtained without a prescription. 

 

Arsenic trioxide Accord must be given under the supervision of a physician experienced in the 

treatment of acute leukaemias. 

 

Do not use Arsenic trioxide Accord 
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 using Arsenic trioxide Accord, 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 Arsenic trioxide Accord. 

- 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  Arsenic trioxide Accord. 



27 

 

- 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 Arsenic trioxide Accord, may cause other cancers. You should report any 

new and exceptional symptoms and circumstances whenever you see your doctor. 

 

Children and adolescents 

Arsenic trioxide Accord is not recommended in children and adolescents below 18 years of age. 

 

Other medicines and Arsenic trioxide Accord 
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 hayfever, 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 Arsenic trioxide Accord. 

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. 

 

Arsenic trioxide Accord with food and drink 
There are no restrictions on your food or drink while you are receiving Arsenic trioxide Accord. 

 

Pregnancy 

Ask your doctor or pharmacist for advice before taking any medicine.  

Arsenic trioxide Accord 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 Arsenic 

trioxide Accord. 

If you are pregnant or you become pregnant during the treatment with Arsenic trioxide Accord, you 

must ask your doctor for advice. 

Men should also use effective contraception during treatment with Arsenic trioxide Accord.  

 

Breast-feeding 

Ask your doctor or pharmacist for advice before taking any medicine. The arsenic in Arsenic trioxide 

Accord passes into breast milk. 

Because Arsenic trioxide Accord can harm nursing infants, do not breast-feed while on Arsenic 

trioxide Accord. 

 

Driving and using machines 

Arsenic trioxide Accord 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 Arsenic trioxide Accord 

injection, you should wait until the symptoms go away before driving or using machines. 

 

Arsenic trioxide Accord contains sodium 



28 

 

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-

free”. 

 

 

3. How to use Arsenic trioxide Accord 
 

Duration and frequency of treatment 

 

Patients with newly diagnosed acute promyelocytic leukaemia 

Your doctor will give you Arsenic trioxide Accord 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 Arsenic trioxide Accord, you will be given 4 

additional treatment cycles 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 Arsenic trioxide Accord. 

 

Patients with acute promyelocytic leukaemia, whose disease has not responded to other therapies 

Your doctor will give you Arsenic trioxide Accord 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 Arsenic trioxide Accord, 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 Arsenic trioxide 

Accord. 

 

Method and route of administration 

 

Arsenic trioxide Accord must be diluted with a solution containing glucose or a solution containing 

sodium chloride. 

 

Arsenic trioxide Accord 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. 

 

Arsenic trioxide Accord must not be mixed with, or infused through the same tube with other 

medicines. 

 

If your doctor gives you more Arsenic trioxide Accord than he/she should 
You may experience convulsions, muscle weakness and confusion. If this happens, treatment with 

Arsenic trioxide Accord 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 or pharmacist. 

 

 

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 



29 

 

- fever 
- sudden weight gain 
- water retention 
- fainting 
- palpitations (strong heartbeat you can feel in your chest) 

 

While on treatment with Arsenic trioxide Accord, you may experience some of the following 

reactions: 

 

Very common (may affect more than 1 in 10 people): 

- fatigue (weariness), pain, fever, headache 
- 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 
 

Reporting of side effects 

If you get any side effects, talk to your doctor or 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 Arsenic trioxide Accord 
 

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 first opening: Once opened the product should be used immediately. 

 

Shelf life after dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 

25 °C and 48 hours at 2°C to 8°C. 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°C-8°C, unless dilution 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


30 

 

has taken place in controlled and validated aseptic conditions. 

 

 

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 Arsenic trioxide Accord contains 

 

- The active substance is arsenic trioxide  One mL of concentrate contains 1 m arsenic 
trioxide.One vial contains 10 mg of arsenic trioxide. 

- The other ingredients are sodium hydroxide, concentrated hydrochloric acid (for pH adjustment)  
and water for injections. See section 2, “Arsenic trioxide Accord contains sodium”. 

 

What Arsenic trioxide Accord  looks like and contents of the pack 

Arsenic trioxide Accord is a concentrate for solution for infusion. Arsenic trioxide Accord is supplied 

in glass vials as a concentrated, sterile, clear, colourless, aqueous solution . 

Each carton contains 1, 5 or 10 vials.  

 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder  

 

Accord Healthcare S.L.U. 

World Trade Center, Moll de Barcelona S/N,  

Edifici Est, 6a planta,  

08039 Barcelona, 

Spain 

 

Manufacturer 

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,  

95-200 Pabianice, 

Poland  

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  
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  

http://www.ema.europa.eu/


31 

 

--------------------------------------------------------------------------------------------------------------------------- 

The following information is intended for healthcare professionals only: 

 

ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 

ARSENIC TRIOXIDE ACCORD SINCE NO PRESERVATIVE IS PRESENT. 

 

Dilution of Arsenic trioxide Accord 
Arsenic trioxide Accord must be diluted before administration. PVC-free plastic bags should be used. 

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 through the rubber stopper and draw up 

all of the content. Arsenic trioxide Accord 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 Arsenic trioxide Accord 

For single use only. Arsenic trioxide Accord must not be mixed with or concomitantly administered in 

the same intravenous line with other medicinal products. 

 

Arsenic trioxide Accord 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, Arsenic trioxide Accord is chemically and physically stable 

for 24 hours at 25°C and 48 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. 


	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 MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET