Arsenic trioxide medac

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Arsenic trioxide medac 1 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of concentrate 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 concentrate). 
 
Sterile, clear, colourless, aqueous solution, free from particles. The pH of the solution is 6.0-8.0. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Arsenic trioxide medac 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 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 pro-myelocytic 
leukaemia/retinoic-acid-receptor-alpha (PML/RARα) 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 medac 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 APL 
 
Induction treatment schedule 
Arsenic trioxide medac must be administered intravenously at a dose of 0.15 mg/kg/day, given daily 
until complete remission (CR) is achieved. If CR has not occurred by day 60, dosing must be 
discontinued. 
  



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Consolidation schedule 
Arsenic trioxide medac 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 APL 
 
Induction treatment schedule 
Arsenic trioxide medac must be administered intravenously at a fixed dose of 0.15 mg/kg/day given 
daily until CR is achieved (less than 5% blasts present in cellular bone marrow with no evidence of 
leukaemic cells). If CR 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 medac 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 medac 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 (CTC) is observed and judged to be possibly related to Arsenic trioxide medac treatment. 
Patients who experience such reactions that are considered Arsenic trioxide medac 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 electrocardiogram (ECG), 
electrolyte 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 Arsenic trioxide medac, caution is advised in the use of Arsenic trioxide 
medac 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 Arsenic 
trioxide medac in patients with renal impairment. 
 
Paediatric population 
 
The safety and efficacy of Arsenic trioxide medac 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 medac 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. 
  



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Precautions to be taken before handling or administering the medicinal product 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances 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 medac 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 
medac therapy during treatment of the APL differentiation syndrome. As soon as signs and symptoms 
have subsided, treatment with Arsenic trioxide medac 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 medac might be resumed at full dosage. In the case of the reappearance of symptoms Arsenic 
trioxide medac 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 medac 
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 
medac. 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. 
 



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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 studies, 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 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 medac, 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 
medac. During therapy with Arsenic trioxide medac, 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 medac 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 medac 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 
medac 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. ECGs must be obtained twice weekly, and 
more frequently for clinically unstable patients, during induction and consolidation. 
 



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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 medac must be discontinued before 
the scheduled end of therapy at any time that a hepatotoxicity grade 3 or greater on the CTC 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 medac 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 medac should be resumed at full dosage. In case of reappearance of hepatotoxicity, 
Arsenic trioxide medac must be permanently discontinued. 
 
Dose delay and modification 
 
Treatment with Arsenic trioxide medac 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 CTC is observed 
and judged to be possibly related to Arsenic trioxide medac 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 Arsenic 
trioxide medac 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 medac in patients on dialysis has not been studied. 
 
Hepatic impairment 
 
Since no data are available across all hepatic impairment groups and hepatotoxic effects may occur 
during the treatment with arsenic trioxide caution is advised in the use of Arsenic trioxide medac 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 medac in the elderly population. Caution is 
needed in these patients. 
 



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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 normalised 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 10³/µl 500 mg four times a day 
> 50 x 10³/µl 1,000 mg four times a day 

 
Development of second primary malignancies 
 
The active ingredient of Arsenic trioxide medac, 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 Arsenic trioxide medac and other 
therapeutic medicinal products have been conducted. 
 
Medicinal products known to cause QT/QTc interval prolongation, hypokalaemia or 
hypomagnesaemia 
 
QT/QTc prolongation is expected during treatment with arsenic trioxide, and torsade de pointes and 
complete heart block have been reported. Patients who are receiving, or who have received, medicinal 
products known to cause hypokalaemia or hypomagnesaemia, such as diuretics or amphotericin B, 
may be at higher risk for torsade de pointes. Caution is advised when Arsenic trioxide medac 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 
hypokalaemia 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 medac 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 medac 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 medac. 
 
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 medac. 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 children from Arsenic trioxide medac, breast-feeding must be discontinued prior to and 
throughout administration. 
 
Fertility 
 
No clinical or non-clinical fertility studies have been conducted with Arsenic trioxide medac. 
 
4.7 Effects on ability to drive and use machines 
 
Arsenic trioxide medac 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. 
 



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In general, treatment-emergent adverse events tended to decrease over time, in relapsed/refractory 
APL patients perhaps accounted for by amelioration of the underlying disease process. Patients tended 
to tolerate consolidation and maintenance treatment with less toxicity than in induction. This is 
probably due to the confounding of adverse events by the uncontrolled disease process early on in the 
treatment course and the myriad concomitant medicinal products required to control symptoms and 
morbidity. 
 
In a phase 3, multicentre, noninferiority trial comparing 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 
Convulsion Common Not known 
Encephalopathy, Wernicke 
encephalopathy 

Not known Not known 



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Eye disorders 
Vision blurred Common Not known 
Cardiac disorders 
Tachycardia Very Common Common 
Pericardial effusion Common Common 
Ventricular extrasystoles Common Not known 
Cardiac failure Not known Not known 
Ventricular tachycardia Not known Not known 
Vascular disorders 
Vasculitis Common Common 
Hypotension Common Not known 
Respiratory, thoracic and mediastinal disorders 
Differentiation syndrome Very Common Very Common 
Dyspnoea Very Common Common 
Hypoxia Common Common 
Pleural effusion Common Common 
Pleuritic pain Common Common 
Pulmonary alveolar haemorrhage Common Common 
Pneumonitis Not known Not known 
Gastrointestinal disorders 
Diarrhoea Very Common Common 
Vomiting Very Common Not known 
Nausea Very Common Not known 
Abdominal pain Common Common 
Skin and subcutaneous tissue disorders 
Pruritus Very Common Not known 
Rash Very Common Not known 
Erythema Common Common 
Face oedema Common Not known 
Musculoskeletal and connective tissue disorders 
Myalgia Very Common Common 
Arthralgia Common Common 
Bone pain Common Common 
Renal and urinary disorders 
Renal failure Common Not known 
General disorders and administration site conditions 
Pyrexia Very Common Common 
Pain Very Common Common 
Fatigue Very Common Not known 
Oedema Very Common Not known 
Chest pain Common Common 
Chills Common Not known 
Investigations 
Alanine amino transferase increased Very Common Common 
Aspartate amino transferase increased Very Common Common 
Electrocardiogram QT prolonged Very Common Common 
Hyperbilirubinaemia Common Common 
Blood creatinine increased Common Not known 
Weight increased Common Not known 
Gamma-glutamyltransferase increased* Not known* Not known* 
*In the CALGB study C9710, 2 cases of grade ≥ 3 increased GGT were reported out of the 
200 patients who received arsenic trioxide 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 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/ μl) during induction, 4 of 
whom had values above 100,000/ μl. Baseline WBCcounts 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-marketing 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 paraesthesia/dysesthesia, is a common and well-known effect 
of environmental arsenic. Only 2 relapsed/refractory APL patients discontinued treatment early due to 
this adverse reaction and one went on to receive additional arsenic trioxide on a subsequent protocol. 
Forty-four percent 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 
arsenic trioxide. 
 



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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 medac 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 Arsenic trioxide medac 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/RARα. 
 

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


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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, randomised, non-inferiority phase 3 clinical study comparing the efficacy and 
safety of arsenic trioxide combined with 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 patients with variant translocations like t(11;17) 
(PLZF/RARα). Patients with significant arrhythmias, ECG 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 ECG, 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 
haematological recovery from the previous course defined as absolute neutrophil count > 1.5 x 109/L 
and platelets > 100 x 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 
Haematalogic 
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 
 



14 

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 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 CR received consolidation therapy with 
arsenic trioxide 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. 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 study 

N = 12 
Multicentre study 

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

0.16 (0.06 – 0.20) 0.15 

CR 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 study included 5 paediatric patients (< 18 years old), 3 of whom achieved CR. No 
children of less than 5 years of age were treated. 
 



15 

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. 
 

 
 



16 

Cytogenetic confirmation of conversion to a normal genotype and reverse transcriptase–polymerase 
chain reaction (RT-PCR) detection of PML/RARα conversion to normal are shown in table 5 below. 
 
Cytogenetics after arsenic trioxide therapy 
 
Table 5 
 Single centre pilot study 

N with CR = 11 
Multicentre study 

N with CR = 34 
Conventional   
Cytogenetics   
[t(15;17)]   
Absent 8 (73 %) 31 (91 %) 
Present 1 (9 %) 0 % 
Not evaluable 2 (18 %) 3 (9 %) 

RT-PCR for PML/  
 
 

8 (73 %) 
3 (27 %) 

0 

 

RARα  

Negative 
Positive 
Not evaluable 

 

 
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 under 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 
 
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 
 



17 

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 medac. 
 
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-normalised (per mg dose) area under the 
curve (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 characterised 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 
 



18 

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 Arsenic 
trioxide medac. 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 compatibility 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 48 hours at 30 °C and 72 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. 
 
6.5 Nature and contents of container 
 
10 ml concentrate in a clear, type I glass vial with a chlorobutyl rubber stopper, an aluminium shell 
and a plastic flip-off button. Each pack contains 10 vials. 
 
6.6 Special precautions for disposal and other handling 
 
Preparation of Arsenic trioxide medac 
 
Aseptic technique must be strictly observed throughout handling of Arsenic trioxide medac since no 
preservative is present. 
 



19 

Arsenic trioxide medac 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.  
 
Arsenic trioxide medac 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 
 
Arsenic trioxide medac 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. 
 
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 
 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1475/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
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. 
 
  

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


20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



21 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
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 (PSURs) 
 
The requirements for submission of PSURs 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 marketing authorisation holder (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. 

 
 
 
 
 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Arsenic trioxide medac 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 
 
Excipients: sodium hydroxide, hydrochloric acid, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
 
10 vials of 10 ml (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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
 



25 

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 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1475/001 
 
 
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 
 



26 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Arsenic trioxide medac 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 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

Package leaflet: Information for the user 
 

Arsenic trioxide medac 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 any further questions, 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 Arsenic trioxide medac is and what it is used for  
2. What you need to know before you are given Arsenic trioxide medac 
3. How Arsenic trioxide medac is used  
4. Possible side effects  
5. How to store Arsenic trioxide medac 
6. Contents of the pack and other information 
 
 
1. What Arsenic trioxide medac is and what it is used for 
 
Arsenic trioxide medac contains the active substance arsenic trioxide which is an anticancer medicine. 
The mechanism of action of Arsenic trioxide medac is not completely understood. 
 
Arsenic trioxide medac 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 Arsenic trioxide medac 
 
Please tell your doctor,pharmacist or nurse if you are taking or have recently taken any other 
medicines, including medicines obtained without a prescription. 
 
You will not be given Arsenic trioxide medac 
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, pharmacist or nurse before you are given Arsenic trioxide medac, if 
• you have impaired kidney function. 
• you have any liver problems. 
 



29 

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 medac. 
• You should have an electrical recording of the heart (electrocardiogram, ECG) performed 

before your first dose. 
• Blood tests (potassium, calcium, liver function) should be repeated during your treatment with 

Arsenic trioxide medac. 
• 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 medac, 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 
Arsenic trioxide medac is not recommended in children and adolescents below 18 years of age. 
 
Other medicines and Arsenic trioxide medac 
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 or pharmacist 
• 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 medac. 
You must be sure to tell your doctor or pharmacist 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 or pharmacist. 

 
Arsenic trioxide medac with food and drink 
There are no restrictions on your food or drink while you are receiving Arsenic trioxide medac. 
 
Pregnancy 
Ask your doctor or pharmacist for advice before taking any medicine. Arsenic trioxide medac 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 medac. 
If you are pregnant or you become pregnant during the treatment with Arsenic trioxide medac, you 
must ask your doctor or pharmacist for advice. 
Men should also use effective contraception during treatment with Arsenic trioxide medac. 
 



30 

Breast-feeding 
Ask your doctor or pharmacist for advice before taking any medicine. The arsenic in Arsenic trioxide 
medac passes into breast milk. 
Because Arsenic trioxide medac can harm breastfed children, do not breast-feed while on Arsenic 
trioxide medac. 
 
Driving and using machines 
Arsenic trioxide medac 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 an Arsenic trioxide medac injection, 
you should wait until the symptoms go away before driving or using machines. 
 
Arsenic trioxide medac contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’. 
 
 
3. How Arsenic trioxide medac is used 
 
Arsenic trioxide medac must be given under the supervision of a physician experienced in the 
treatment of acute leukaemias. 
 
Duration and frequency of treatment 
 
Patients with newly diagnosed acute promyelocytic leukaemia 
Your doctor will give you Arsenic trioxide medac 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 medac, 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 medac. 
 
Patients with acute promyelocytic leukaemia, whose disease has not responded to other therapies 
Your doctor will give you Arsenic trioxide medac 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 medac, 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 
medac. 
 
Method and route of administration 
Arsenic trioxide medac must be diluted with a solution containing glucose or a solution containing 
sodium chloride. 
 
Arsenic trioxide medac 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 medac must not be mixed with, or infused through the same tube with other 
medicines. 
 
If you are given  more Arsenic trioxide medac than you should 
You may experience convulsions, muscle weakness and confusion. If this happens, treatment with 
Arsenic trioxide medac 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. 
 
 



31 

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 Arsenic trioxide medac, 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 
• 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. 

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


32 

 
 
5. How to store Arsenic trioxide medac 
 
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 
medicinal product does not require any special storage conditions. 
 
Once opened the product should be used immediately. 
 
After dilution, if not used immediately, storage times and conditions before use are the responsibility 
of your doctor and would normally not be longer than 24 hours at 2ºC–8ºC, unless dilution has taken 
place in a sterile environment. 
 
This medicine will not be used if it appears to contain 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 protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Arsenic trioxide medac contains 
- The active substance is arsenic trioxide. One ml of concentrate contains 1 mg arsenic trioxide. 

One vial contains 10 mg of arsenic trioxide. 
- The other ingredients are sodium hydroxide, hydrochloric acid and water for injections. See 

section 2 “Arsenic trioxide medac contains sodium”. 
 
What Arsenic trioxide medac looks like and contents of the pack 
Arsenic trioxide medac is a concentrate for solution for infusion (sterile concentrate). It is supplied in 
glass vials as a concentrated, sterile, clear, colourless, aqueous solution. Each carton contains 
10 single-use glass vials. 
 
Marketing Authorisation Holder and Manufacturer 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
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 healthcare professionals only: 
 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 
ARSENIC TRIOXIDE MEDAC SINCE NO PRESERVATIVE IS PRESENT. 
 
Dilution of Arsenic trioxide medac 



33 

Arsenic trioxide medac 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 draw up all of the content. Arsenic 
trioxide medac 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. 
 
Arsenic trioxide medac is for single use only. Unused portions of each vial must be discarded 
properly. Do not save any unused portions for later administration. 
 
Use of Arsenic trioxide medac 
Arsenic trioxide medac must not be mixed with or concomitantly administered in the same intravenous 
line with other medicinal products. 
 
Arsenic trioxide medac 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. 
 
Chemical and physical in-use stability has been demonstrated for 48 hours at 30 °C and 72 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 2-8°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