Arsenic trioxide Mylan

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Arsenic trioxide Mylan 1 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 ml of concentrate contains 1 mg of arsenic trioxide. 
 
Each 10 ml vial 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 with a pH of 7.5 to 8.5. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Arsenic trioxide Mylan 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 Mylan 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 Mylan 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 Mylan 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.  



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Relapsed/refractory acute promyelocytic leukaemia (APL) 
 
Induction treatment schedule  
Arsenic trioxide Mylan 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 Mylan 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 Mylan 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 Mylan 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  
 
Hepatic impairment  
 
Since no data are available across all hepatic impairment groups and hepatotoxic effects may occur 
during the treatment with Arsenic trioxide Mylan, caution is advised in the use of Arsenic trioxide 
Mylan 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 Mylan in patients with renal impairment.  
 
Paediatric population  
 
The safety and efficacy of Arsenic trioxide Mylan 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 Mylan 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 all-trans-retinoic acid 
(ATRA), APL differentiation syndrome was observed in 19% including 5 severe cases. At the first 
signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal 
chest auscultatory findings or radiographic abnormalities), treatment with 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 induction treatment was terminated 



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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. 
 
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. 
 
Hepatic impairment  



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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 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 103/μl  500 mg four times a day  
> 50 x 103/μl  1000 mg four times a day  

 
Development of second primary malignancies  
The active ingredient of Arsenic trioxide Mylan, 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 vial, 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 Mylan is 



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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.   
 
Medicinal products known to cause hepatotoxic effects  
Hepatotoxic effects may occur during the treatment with arsenic trioxide, caution is advised when 
Arsenic trioxide Mylan 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 Mylan 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 Mylan.  
 
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 Mylan. 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 Mylan, breast-feeding must be discontinued prior to and 
throughout administration.  
 
Fertility  
No clinical or non-clinical fertility studies have been conducted with Arsenic trioxide Mylan. 
 
4.7 Effects on ability to drive and use machines 
 
Arsenic trioxide Mylan 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 reactions 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 reactions by the uncontrolled disease process early on in 



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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 
Convulsion Common Not known 
Encephalopathy, Wernicke encephalopathy Not known Not known 
Eye disorders   
Vision blurred Common Not known 
Cardiac disorders   
Tachycardia  Very Common Common 
Pericardial effusion  Common Common 
Ventricular extrasystoles  Common Not known 



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 All grades Grades ≥ 3 
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. 
 
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 



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whom had values above 100,000/μl. Baseline white blood cell (WBC) counts did not correlate with 
development of leukocytosis on study, and WBC counts during consolidation therapy were not as high 
as during induction. In these studies, leukocytosis was not treated with chemotherapeutic medicinal 
products. Medicinal products that are used to lower the white blood cell count often exacerbate the 
toxicities associated with leukocytosis, and no standard approach has proven effective. One patient 
treated under a compassionate use program died from cerebral infarct due to leukocytosis, following 
treatment with chemotherapeutic medicinal products to lower WBC count. Observation is the 
recommended approach with intervention only in selected cases.  
 
Mortality in the pivotal studies 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 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 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.  
 
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 



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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 Mylan 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 Succimer or Dimercaptosuccinic Acid 
(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 Mylan is not completely understood. Arsenic trioxide 
causes morphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of 
apoptosis in NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage 
or degradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha (PML/RAR 
alpha). 
 
Clinical efficacy and safety  
 
Newly diagnosed non high risk APL patients  
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-RARα by RT-PCR or micro speckled 
PML nuclear distribution in leukemic cells were included. No data are available on patient with 
variant translocations like t(11;17) (PLZF/RARα). Patients with significant arrhythmias, EKG 
abnormalities (congenital long QT syndrome, history or presence of significant ventricular or atrial 
tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTc > 450 msec on 
screening EKG, right bundle branch block plus left anterior hemiblock, bifascicular block) or 
neuropathy were excluded from the study. Patients in the ATRA + 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, 

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12 

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 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-week period. Consolidation therapy 
began 6 weeks (range, 3-8) after induction in the single institution study and 4 weeks (range, 3-6) in 
the multicentre study. Complete remission (CR) was defined as the absence of visible leukaemic cells 
in the bone marrow and peripheral recovery of platelets and white blood cells. 
Patients in the single centre study had relapsed following 1-6 prior therapy regimens and 2 patients 
had relapsed following stem cell transplantation. Patients in the multicentre study had relapsed 
following 1-4 prior therapy regimens and 5 patients had relapsed following stem cell transplantation. 
The median age in the single centre study was 33 years (age range 9 to 75). The median age in the 
multicentre study was 40 years (age range 5 to 73).  
 
The results are summarised in the table 4 below.  
 
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 



13 

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. 
 

 
 
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. 
 



14 

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 8 (73%) 31 (91%) 
Present 1 (9%) 0% 
Not evaluable 2 (18%) 3 (9%) 

RT-PCR for PML/ 
RARα   

Negative 8 (73%) 27 (79%) 
Positive 3 (27%) 4 (12%) 
Not evaluable 0 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 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  
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 Mylan. 
 
Elimination  



15 

Approximately 15% of the administered Arsenic trioxide Mylan dose is excreted in the urine as 
unchanged AsIII. The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the 
urine. The plasma concentration of AsIII declines from peak plasma concentration in a biphasic manner 
with a mean terminal elimination half-life of 10 to 14 hours. The total clearance of AsIII over the 
single-dose range of 7-32 mg (administered as 0.15 mg/kg) is 49 L/h and the renal clearance is 9 L/h. 
Clearance is not dependent on the weight of the subject or the dose administered over the dose range 
studied. The mean estimated terminal elimination half-lives of the metabolites MMAV and DMAV are 
32 hours and 70 hours, respectively.  
 
Renal impairment  
Plasma clearance of AsIII was not altered in patients with mild renal impairment (creatinine clearance 
of 50-80 mL/min) or moderate renal impairment (creatinine clearance of 30-49 mL/min). The plasma 
clearance of AsIII in patients with severe renal impairment (creatinine clearance less than 30 mL/min) 
was 40% lower when compared with patients with normal renal function (see section 4.4).  
 
Systemic exposure to MMAV and DMAV tended to be larger in patients with renal impairment; the 
clinical consequence of this is unknown but no increased toxicity was noted.  
 
Hepatic impairment  
Pharmacokinetic data from patients with hepatocellular carcinoma having mild to moderate hepatic 
impairment indicate that AsIII or AsV do not accumulate following twice-weekly infusions. No clear 
trend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed with 
decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC.  
 
Linearity/non-linearity  
In the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) 
appears to be linear. The decline from peak plasma concentration of AsIII occurs in a biphasic manner 
and is characterized by an initial rapid distribution phase followed by a slower terminal elimination 
phase. After administration at 0.15 mg/kg on a daily (n=6) or twice-weekly (n=3) regimen, an 
approximate 2-fold accumulation of AsIII was observed as compared to a single infusion. This 
accumulation was slightly more than expected based on single-dose results. 
 
5.3 Preclinical safety data 
 
Limited reproductive toxicity studies of arsenic trioxide in animals indicate embryotoxicity and 
teratogenicity (neural tube defects, anophthalmia and microphthalmia) at administration of 1-10 times 
the recommended clinical dose (mg/m2). Fertility studies have not been conducted with Arsenic 
trioxide Mylan. Arsenic compounds induce chromosomal aberrations and morphological 
transformations of mammalian cells in vitro and in vivo. No formal carcinogenicity studies of arsenic 
trioxide have been performed. However, arsenic trioxide and other inorganic arsenic compounds are 
recognised as human carcinogens. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium hydroxide  
Hydrochloric acid (for pH adjustment)  
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of incompatibility studies, this medicinal product must not be mixed with other 
medicinal products except those mentioned in section 6.6. 
 



16 

6.3 Shelf life 
 
Unopened vial 
2 years 
 
After first opening 
The product should be used immediately. 
 
After dilution 
Chemical and physical in-use stability has been demonstrated for 24 hours at 15-25°C and 48 hours at 
2°C-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 
 
Do not freeze. 
 
For storage conditions after dilution of the medicinal products, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I clear glass vial closed with bromobutyl stoppers and aluminium flip-off cap containing 10 ml 
of concentrate. Each pack contains 1 or 10 vials. 
Not all pack sizes may be marketed. 
 
 
6.6 Special precautions for disposal and other handling 
 
Preparation of Arsenic trioxide Mylan  
Aseptic technique must be strictly observed throughout handling of Arsenic trioxide Mylan since no 
preservative is present.  
 
Arsenic trioxide Mylan 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 Mylan 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 Mylan 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 
 
Mylan Ireland Limited 
Unit 35/36 grange Parade 



17 

Baldoyle Industrial Estate 
Dublin 13 
Ireland 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1427/001 
EU/1/20/1427/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: {DD month YYYY} 
Date of latest renewal: {DD month YYYY} 
 
 
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 
 
Haupt Pharma Wolfratshausen GmbH  
Pfaffenrieder Straße 5 
82515 Wolfratshausen  
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. 

  



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 Mylan 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 
 
Also contains: sodium hydroxide, hydrochloric acid (as pH adjuster) and water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
 
1 vial 
10 vials 
 
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 
Read the leaflet for the shelf-life of the diluted product. 
 
 



23 

9. SPECIAL STORAGE CONDITIONS 
 
Do not freeze. 
 
 
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 
 
Mylan Ireland Limited 
Unit 35/36 grange Parade 
Baldoyle Industrial Estate 
Dublin 13 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1427/001 1 vial 
EU/1/20/1427/002 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 AND ROUTE(S) OF ADMINISTRATION 
 
Arsenic trioxide Mylan 1 mg/ml sterile concentrate  
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 
 
 
 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



26 

Package leaflet: Information for the patient 
 

Arsenic trioxide Mylan 1 mg/ml concentrate for solution for infusion 
arsenic trioxide 

 
Read all of this leaflet carefully before you are given this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have further questions, please ask your doctor or your pharmacist or nurse.  
- 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 Mylan is and what it is used for  
2. What you need to know before you are given Arsenic trioxide Mylan 
3. How to use Arsenic trioxide Mylan 
4. Possible side effects  
5. How to store Arsenic trioxide Mylan 
6. Contents of the pack and other information 
 
 
1. What Arsenic trioxide Mylan is and what it is used for 
 
Arsenic trioxide Mylan 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 Mylan 
 
Arsenic trioxide Mylan must be given under the supervision of a physician experienced in the 
treatment of acute leukaemias.  
 
You must not receive Arsenic trioxide Mylan 
If you are allergic to arsenic trioxide or any of the other ingredients of this medicine (listed in section 
6).  
 
Warnings and precautions  
You must talk to your doctor or nurse before you are given Arsenic trioxide Mylan, 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 Mylan.  
- You should have an electrical recording of the heart (electrocardiogram ECG) performed before 

your first dose.  
- Blood tests (potassium, magnesium, calcium, liver function) should be repeated during your 

treatment with Arsenic trioxide Mylan. 
- 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 Mylan, may cause other cancers. You should report any 
new and exceptional symptoms and circumstances whenever you see your doctor.  



27 

- Follow-up of your cognitive and mobility functions if you are at risk for vitamin B1 deficiency.  
 
Children and adolescents  
Arsenic trioxide Mylan is not recommended in children and adolescents below 18 years of age.  
 
Other medicines and Arsenic trioxide Mylan 
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 Mylan. 
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 Mylan with food and drink  
There are no restrictions on your food or drink while you are receiving Arsenic trioxide Mylan.  
 
Pregnancy  
Ask your doctor or pharmacist for advice before taking any medicine.  
Arsenic trioxide Mylan 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 Mylan.  
If you are pregnant or you become pregnant during the treatment with Arsenic trioxide Mylan, you 
must ask your doctor for advice.  
Men should also use effective contraception during treatment with Arsenic trioxide Mylan.  
 
Breast-feeding  
Ask your doctor or pharmacist for advice before taking any medicine.  
The arsenic in Arsenic trioxide Mylan passes into breast milk.  
Because Arsenic trioxide Mylan can harm nursing infants, do not breast-feed while on Arsenic 
trioxide Mylan. 
 
Driving and using machines  
Arsenic trioxide Mylan 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 Mylan injection, you should 
wait until the symptoms go away before driving or using machines.  
 
Arsenic trioxide Mylan contains sodium  
This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 
‘sodium-free’. 
 
 



28 

3. How to use Arsenic trioxide Mylan 
 
Duration and frequency of treatment  
 
Patients with newly diagnosed acute promyelocytic leukaemia  
Your doctor will give you Arsenic trioxide Mylan 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 Mylan, you will be given 4 
additional treatment cycles. Each cycle consists of 20 doses given 5 days per week (followed by 2 
days interruption) for 4 weeks followed by 4 weeks interruption. Your doctor will decide exactly how 
long you must continue on therapy with Arsenic trioxide Mylan.  
 
Patients with acute promyelocytic leukaemia, whose disease has not responded to other therapies  
Your doctor will give you Arsenic trioxide Mylan 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 Mylan, 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 
Mylan.   
 
Method and route of administration  
 
Arsenic trioxide Mylan must be diluted with a solution containing glucose or a solution containing 
sodium chloride.  
 
Arsenic trioxide Mylan 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 Mylan must not be mixed with or infused through the same tube with other 
medicines.  
 
If your doctor or nurse gives you more Arsenic trioxide Mylan than he/she should  
You may experience convulsions, muscle weakness and confusion. If this happens, treatment with 
Arsenic trioxide Mylan 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 or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Tell your doctor or nurse straight away if you notice the following side effects, as these may be 
signs of a severe condition called “differentiation syndrome”, which might be fatal:  
- difficulty in breathing  
- coughing  
- chest pain  
- fever  
 
Tell your doctor or nurse straight away if you notice one or more of the following side effects, as 
these may be signs of allergic reaction:  
- difficulty in breathing  
- fever  
- sudden weight gain  
- water retention  
- fainting  
- palpitations (strong heartbeat you can feel in your chest) 



29 

 
While on treatment with Arsenic trioxide Mylan, 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. 
 
 
5. How to store Arsenic trioxide Mylan 
 
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.  
 
Do not freeze.  
 
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 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. 
 

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


30 

 
6. Contents of the pack and other information 
 
What Arsenic trioxide Mylan contains 
- The active substance is arsenic trioxide. Each ml of concentrate contains 1 mg of arsenic 

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

section 2 ‘Arsenic trioxide Mylan contains sodium’. 
 
What Arsenic trioxide Mylan looks like and contents of the pack 
Arsenic trioxide Mylan is a concentrate for solution for infusion (sterile concentrate). It is supplied in 
glass vials as a concentrated, clear, colourless, aqueous solution. Each carton contains 1 or 10 
single-use glass vials. 
 
Marketing Authorisation Holder  
Mylan Ireland Limited 
Unit 35/36 grange Parade 
Baldoyle Industrial Estate 
Dublin 13 
Ireland 
 
Manufacturer 
Haupt Pharma Wolfratshausen GmbH 
Pfaffenrieder Straße 5 
82515 Wolfratshausen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Mylan bvba/sprl 
Tél/Tel: + 32 (0)2 658 61 00 
 

Lietuva 
BGP Products UAB  
Tel: +370 5 205 1288 
 

България 
Майлан ЕООД 
Тел: +359 2 44 55 400 
 

Luxembourg/Luxemburg 
Mylan bvba/sprl 
Tel: + 32 (0)2 658 61 00 
(Belgique/Belgien) 
 

Česká republika 
Mylan Healthcare CZ s.r.o. 
Tel: + 420 222 004 400 

Magyarország 
Mylan EPD Kft 
Tel: + 36 1 465 2100 
  

Danmark 
Mylan Denmark ApS 
Tlf: +45 28 11 69 32 
 

Malta 
V.J. Salomone Pharma Ltd 
Tel: + 356 21 22 01 74 
 

Deutschland 
Mylan Healthcare GmbH 
Tel: + 49- 800 0700 800 
 

Nederland 
Mylan BV 
Tel: +31 (0)20 426 3300 



31 

Eesti 
BGP Products Switzerland GmbH Eesti 
filiaal  
Tel: + 372 6363 052 
 

Norge 
Mylan Healthcare Norge AS 
Tel: + 47 66 75 33 00 
 

Ελλάδα  
Generics Pharma Hellas ΕΠΕ  
Τηλ:  +30 210 993 6410  
 

Österreich 
Arcana Arzneimittel GmbH 
Tel: +43 1 416 2418 
 

España 
Mylan Pharmaceuticals, S.L 
Tel: + 34 900 102 712 
 

Polska 
Mylan Healthcare Sp. z o.o. 
Tel: + 48 22 546 64 00 
 

France 
Mylan S.A.S 
Tel: +33 4 37 25 75 00 
 

Portugal 
Mylan, Lda. 
Tel: + 351 21 412 72 56 
 

Hrvatska 
Mylan Hrvatska d.o.o. 
Tel: +385 1 23 50 599 
  

România 
BGP Products SRL 
Tel: +40 372 579 000 
 

Ireland 
Mylan Ireland Limited 
Tel:  +353 (0) 87 1694982  

Slovenija 
Mylan Healthcare d.o.o. 
Tel: + 386 1 23 63 180 
 
 

Ísland 
Icepharma hf 
Tel: +354 540 8000 
 
 

Slovenská republika 
Mylan s.r.o. 
Tel: +421 2 32 199 100 

Italia 
Mylan Italia S.r.l. 
Tel: + 39 02 612 46921 
 

Suomi/Finland 
Mylan Finland OY 
Puh/Tel: +358 20 720 9555 
 

Κύπρος 
Varnavas Hadjipanayis Ltd 
Τηλ: +357 2220 7700 
 

Sverige 
Mylan AB  
Tel: + 46 855 522 750 
 

Latvija 
Mylan Healthcare SIA  
Tel: +371 676 055 80 
 

United Kingdom 
Generics [UK] Ltd 
Tel: +44 1707 853000 

 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  



32 

 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website.  
 
---------------------------------------------------------------------------------------------------------------------------  
 
The following information is intended for healthcare professionals only 
 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 
Arsenic trioxide Mylan SINCE NO PRESERVATIVE IS PRESENT.  
 
Dilution of Arsenic trioxide Mylan 
Arsenic trioxide Mylan 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 Mylan 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 Mylan 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 Mylan  
Arsenic trioxide Mylan must not be mixed with or concomitantly administered in the same intravenous 
line with other medicinal products. 
 
Arsenic trioxide Mylan 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 Mylan is chemically and physically stable for 
24 hours at 15-25°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