Leaflet ARSENIC TRIOXIDE ACCORD 1mg / ml concentrate for solution for infusion

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

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

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

For the full list of excipients, see section 6.1

Concentrate for solution for infusion

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

Arsenic trioxide is indicated for induction of remission, and consolidation in adult patients with:

* Newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (APL) (whiteblood cell count, ≤ 10 x 103/µl) in combination with all-trans-retinoic acid (ATRA)

* Relapsed/refractory acute promyelocytic leukaemia (APL) (previous treatment shouldhave included a retinoid and chemotherapy)characterised by the presence of the t(15;17) translocation and/or the presence of the promyelocyticleukaemia/retinoic-acid-receptor-alpha (PML/RAR-alpha) gene.

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

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

The same dose is recommended for adults and elderly.

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

Induction treatment schedule

Arsenic trioxide must be administered intravenously at a dose of 0.15 mg/kg/day, given daily untilcomplete remission is achieved. If complete remission has not occurred by day 60, dosing must bediscontinued.

Consolidation schedule

Arsenic trioxide must be administered intravenously at a dose of 0.15 mg/kg/day, 5 days per week.

Treatment should be continued for 4 weeks on and 4 weeks off, for a total of 4 cycles.

Relapsed/refractory acute promyelocytic leukaemia (APL)

Induction treatment schedule

Arsenic trioxide must be administered intravenously at a fixed dose of 0.15 mg/kg/day given dailyuntil complete remission is achieved (less than 5% blasts present in cellular bone marrow with noevidence of leukaemic cells). If complete remission has not occurred by day 50, dosing must bediscontinued.

Consolidation schedule

Consolidation treatment must begin 3 to 4 weeks after completion of induction therapy. Arsenictrioxide is to be administered intravenously at a dose of 0.15 mg/kg/day for 25 doses given 5 daysper week, followed by 2 days interruption, repeated for 5 weeks.

Dose delay, modification and reinitiation

Treatment with arsenic trioxide must be temporarily interrupted before the scheduled end of therapyat any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity

Criteria is observed and judged to be possibly related to Arsenic trioxide treatment. Patients whoexperience such reactions that are considered arsenic trioxide related must resume treatment onlyafter resolution of the toxic event or after recovery to baseline status of the abnormality thatprompted 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 dailydose can be escalated back to 100% of the original dose. Patients who experience a recurrence oftoxicity must be removed from treatment.

For ECG, electrolytes abnormalities and hepatotoxicity see section 4.4.

Since no data are available across all hepatic impairment groups and hepatotoxic effects may occurduring the treatment with Arsenic trioxide, caution is advised in the use of Arsenic trioxide inpatients with hepatic impairment (see section 4.4 and 4.8).

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

The safety and efficacy of Arsenic trioxide in children aged up to 17 years has not been established.

Currently available data for children aged 5 to 16 years are described in section 5.1 but norecommendation on a posology can be made. No data are available for children under 5 years.

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

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

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

Clinically unstable APL patients are especially at risk and will require more frequent monitoring ofelectrolyte and glycaemia levels as well as more frequent haematologic, hepatic, renal and coagulationparameter tests.

Leukocyte activation syndrome (APL differentiation syndrome)27 % of patients with APL, in the relapsed/refractory setting, treated with arsenic trioxide haveexperienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocyticleukaemia (RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weightgain, pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis. Thissyndrome can be fatal. In newly diagnosed APL patients treated with arsenic trioxide andall-trans-retinoic acid ( ATRA), APL differentiation syndrome was observed in 19 % including5 severe cases. At the first signs that could suggest the syndrome (unexplained fever, dyspnoeaand/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), treatmentwith arsenic trioxide must be temporarily discontinued and high-dose steroids (dexamethasone 10 mgintravenously twice a day) must be immediately initiated, irrespective of the leukocyte count andcontinued for at least 3 days or longer until signs and symptoms have abated. If clinicallyjustified/required, concomitant diuretic therapy is also recommended. The majority of patients do notrequire permanent termination of arsenic trioxide therapy during treatment of the APL differentiationsyndrome. As soon as signs and symptoms have subsided, treatment with arsenic trioxide can beresumed at 50 % of the previous dose during the first 7 days. Thereafter, in the absence of worseningof the previous toxicity, arsenic trioxide might be resumed at full dosage. In the case of thereappearance of symptoms arsenic trioxide should be reduced to the previous dosage. In order toprevent 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 ofarsenic trioxide application to the end of induction therapy in APL patients. It is recommended thatchemotherapy not be added to treatment with steroids since there is no experience withadministration of both steroids and chemotherapy during treatment of the leukocyte activationsyndrome due to arsenic trioxide. Post-marketing experience suggests that a similar syndrome mayoccur in patients with other types of malignancy. Monitoring and management for these patientsshould be as described above.

Electrocardiogram (ECG) abnormalities

Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QTprolongation 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 torsadede pointes is related to the extent of QT prolongation, concomitant administration of QT prolongingmedicinal 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 quinoloneantibiotics (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, congestiveheart failure, administration of potassium-wasting diuretics, amphotericin B or other conditions thatresult 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) intervalprolongation greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeksafter arsenic trioxide infusion, and then returned to baseline by the end of 8 weeks after arsenictrioxide infusion. One patient (receiving multiple, concomitant medicinal products, includingamphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APLwith arsenic trioxide. In newly diagnosed APL patients 15.6 % showed QTc prolongation witharsenic trioxide in combination with ATRA (see section 4.8). In one newly diagnosed patientinduction treatment was terminated because of severe prolongation of the QTc interval andelectrolyte 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 serumelectrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; pre-existingelectrolyte abnormalities must be corrected and, if possible, medicinal products that are known toprolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or riskfactors 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 andmagnesium concentrations must be kept above 1.8 mg/dl. Patients who reach an absolute QT intervalvalue > 500 msec must be reassessed and immediate action must be taken to correct concomitant riskfactors, if any, while the risk/benefit of continuing versus suspending arsenic trioxide therapy must beconsidered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised andmonitored continuously, serum electrolytes must be assessed, arsenic trioxide therapy must betemporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalitiesare corrected, and the syncope and irregular heartbeat cease. After recovery, treatment should beresumed at 50 % of the preceding daily dose. If QTc prolongation does not recur within 7 days ofrestarting treatment at the reduced dose, treatment with arsenic trioxide can be resumed at 0.11 mg/kgbody weight per day for a second week. The daily dose can be escalated back to 100% of the originaldose if no prolongation occurs. There are no data on the effect of arsenic trioxide on the QTc intervalduring the infusion. Electrocardiograms must be obtained twice weekly, and more frequently forclinically 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 4hepatic toxic effects during induction or consolidation treatment with arsenic trioxide in combinationwith ATRA (see section 4.8). However, toxic effects resolved with temporary discontinuation ofeither arsenic trioxide, ATRA or both. Treatment with arsenic trioxide must be discontinued beforethe 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/oralkaline phosphatase are decreased to below 4 times the normal upper level, treatment with arsenictrioxide should be resumed at 50 % of the previous dose during the first 7 days. Thereafter, inabsence of worsening of the previous toxicity, arsenic trioxide should be resumed at full dosage. Incase 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 therapyat 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).

The patient’s electrolyte and glycaemia levels, as well as haematologic, hepatic, renal and coagulationparameter tests must be monitored at least twice weekly, and more frequently for clinically unstablepatients during the induction phase and at least weekly during the consolidation phase.

Since no data are available across all renal impairment groups, caution is advised in the use ofarsenic trioxide in patients with renal impairment. The experience in patients with severe renalimpairment is insufficient to determine if dose adjustment is required.

The use of arsenic trioxide in patients on dialysis has not been studied.

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

There is limited clinical data on the use of arsenic trioxide in the elderly population. Caution is neededin these patients.

Hyperleucocytosis

Treatment with arsenic trioxide has been associated with the development of hyperleucocytosis(≥ 10 x 103/μl) in some relapsed/refractory APL patients. There did not appear to be arelationship between baseline white blood cell (WBC) counts and development ofhyperleucocytosis nor did there appear to be a correlation between baseline WBC count and peak

WBC counts. Hyperleucocytosis was never treated with additional chemotherapy and resolvedon continuation of arsenic trioxide. WBC counts during consolidation were not as high as duringinduction treatment and were < 10 x 103/μl, except in one patient who had a WBC count of 22 x103/μl during consolidation. Twenty relapsed/refractory APL patients (50 %) experiencedleucocytosis; however, in all these patients, the WBC count was declining or had normalized bythe time of bone marrow remission and cytotoxic chemotherapy or leucopheresis was notrequired. In newly diagnosed patients with low to intermediate risk APL leucocytosis developedduring induction therapy in 35 of 74 (47 %) patients (see section 4.8). However all cases weresuccessfully managed with hydroxyurea therapy.

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

Table 1 Recommendation for initiation of hydroxyurea

WBC Hydroxyurea3 500 mg four times a day10-50 x 10 /µl3 1000 mg four times a day> 50 x 10 /µl

Development of second primary malignancies

The active ingredient of Arsenic trioxide Accord, arsenic trioxide, is a human carcinogen. Monitorpatients for the development of second primary malignancies.

Cases of encephalopathy were reported with treatment with arsenic trioxide. Wernicke encephalopathyafter 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 arsenictrioxide initiation. Some cases recovered with vitamin B1 supplementation.

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

No formal assessments of pharmacokinetic interactions between arsenic trioxide and other therapeuticmedicinal products have been conducted.

Medicinal products known to cause QT/QTc interval prolongation, hypokalaemia orhypomagnesaemia

QT/QTc prolongation is expected during treatment with arsenic trioxide, and Torsade de pointes andcomplete heart block have been reported. Patients who are receiving, or who have received, medicinalproducts 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 is co-administered with other medicinal products known to cause QT/QTc interval prolongation such asmacrolide antibiotics, the antipsychotic thioridazine, or medicinal products known to causehypokalaemia or hypomagnesaemia. Additional information about QT prolonging medicinal agents isprovided in Section 4.4.

Medicinal products known to cause hepatotoxic effects

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

Other antileukaemic medicinal products

The influence of arsenic trioxide on the efficacy of other antileukaemic medicinal products isunknown.

Due to the genotoxic risk of arsenic compounds (see section 5.3), women of childbearing potentialmust use effective contraceptive measure treatment with arsenic trioxide and for 6 months followingcompletion of treatment.

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

Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies (see section 5.3).

There are no studies in pregnant women using arsenic trioxide. If this medicinal product is used duringpregnancy or if the patient becomes pregnant while taking this product, the patient must be informed ofthe potential harm to the foetus.

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

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

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

Related adverse reactions of CTC grade 3 and 4 occurred in 37% of relapsed/refractory APLpatients in clinical trials. The most commonly reported reactions were hyperglycaemia,hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leucocytosis occurredin 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/refractorypopulation. Those serious adverse reactions attributed to arsenic trioxide included APL differentiationsyndrome (3), leucocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrialfibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related tohaemorrhage, infections, pain, diarrhoea, nausea.

In general, treatment-emergent adverse events tended to decrease over time, in relapsed/refractory

APL patients perhaps accounted for by amelioration of the underlying disease process. Patientstended to tolerate consolidation and maintenance treatment with less toxicity than in induction. Thisis probably due to the confounding of adverse events by the uncontrolled disease process early on inthe treatment course and the myriad concomitant medicinal products required to control symptomsand morbidity.

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

The following undesirable effects have been reported in the APL0406 study in newly diagnosedpatients 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 andfrequencies 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 decreasingseriousness.

Table 2

All grades Grades ≥ 3

Herpes zoster Common Not known

Sepsis Not known Not known

Pneumonia Not known Not known

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

Hyperglycaemia Very common Very common

Hypokalaemia Very common Very common

Hypomagnesaemia Very common Common

Hypernatraemia Common Common

All grades Grades ≥ 3

Ketoacidosis Common Common

Hypermagnesaemia Common Not known

Dehydration Not known Not known

Fluid retention Not known Not known

Confusional state Not known Not known

Paraesthesia Very common Common

Dizziness Very common Not known

Headache Very common Not known

Convulsion Common Not known

Encephalopathy, Wernicke Not known Not knownencephalopathy

Vision blurred Common Not known

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

Vasculitis Common Common

Hypotension Common Not known

Differentiation syndrome Very common Very common

Dyspnoea Very common Common

Hypoxia Common Common

Pleural effusion Common Common

Pleuritic pain Common Common

Pulmonary alveolar Common Commonhaemorrhage

Pneumonitis Not known Not known

Diarrhoea Very common Common

Vomiting Very common Not known

Nausea Very common Not known

Abdominal pain Common Common

Pruritus Very common Not known

Rash Very common Not known

Erythema Common Common

Face oedema Common Not known

Myalgia Very common Common

Arthralgia Common Common

Bone pain Common Common

Renal failure Common Not known

Pyrexia Very common Common

Pain Very common Common

All grades Grades ≥ 3

Fatigue Very common Not known

Oedema Very common Not known

Chest pain Common Common

Chills Common Not known

Alanine amino transferase Very common Commonincreased

Aspartate amino transferase Very common Commonincreased

Electrocardiogram QT Very common Commonprolonged

Hyperbilirubinaemia Common Common

Blood creatinine increased Common Not known

Weight increased Common Not known

Gamma-glutamyltransferase Not known* Not known*increased*

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

During arsenic trioxide treatment, 14 of the 52 patients in the APL studies in the relapsed setting hadone or more symptoms of APL differentiation syndrome, characterised by fever, dyspnoea, weightgain, pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis (seesection 4.4). Twenty-seven patients had leucocytosis (WBC  10 x 103/l) during induction, 4 ofwhom had values above 100,000/l. Baseline white blood cell (WBC) counts did not correlate withdevelopment of leucocytosis on study, and WBC counts during consolidation therapy were not ashigh as during induction. In these studies, leucocytosis was not treated with chemotherapeuticmedicinal products.

Medicinal products that are used to lower the white blood cell count often exacerbate the toxicitiesassociated with leucocytosis, and no standard approach has proven effective. One patient treatedunder a compassionate use program died from cerebral infarct due to leucocytosis, followingtreatment with chemotherapeutic medicinal products to lower WBC count. Observation is therecommended 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 earlymortality reported in the literature.

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

In post marketing experience, a differentiation syndrome, like retinoic acid syndrome, has also beenreported 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 atorsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes isrelated to the extent of QT prolongation, concomitant administration of QT prolonging medicinalproducts, a history of torsade de pointes, pre-existing QT interval prolongation, congestive heartfailure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemiaor hypomagnesaemia. One patient (receiving multiple, concomitant medicinal products, includingamphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APLwith 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 in15.6 %. In one patient induction treatment was terminated because of severe prolongation of the QTcinterval and electrolyte abnormalities on day 3.

Peripheral neuropathy, characterised by paraesthesia/dysaesthisia, is a common and well knowneffect of environmental arsenic. Only 2 relapsed/refractory APL patients discontinued treatment earlydue to this adverse event and one went on to receive additional arsenic trioxide on a subsequentprotocol. Forty-four per cent of relapsed/refractory APL patients experienced symptoms that could beassociated with neuropathy; most were mild to moderate and were reversible upon cessation oftreatment with arsenic trioxide.

Hepatotoxicity (grade 3-4)

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

Haematological and gastrointestinal toxicity

In newly diagnosed patients with low to intermediate risk APL, gastrointestinal toxicity, grade 3-4neutropenia and grade 3 or 4 thrombocytopenia occurred, however these were 2.2 times less frequentin patients treated with arsenic trioxide in combination with ATRA compared to patients treated with

ATRA + chemotherapy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If symptoms suggestive of serious acute arsenic toxicity (e.g. convulsions, muscle weakness andconfusion) appear, arsenic trioxide must be immediately discontinued and chelating therapy withpenicillamine at a daily dose ≤ 1 g per day may be considered. The duration of treatment withpenicillamine must be evaluated taking into account the urinary arsenic laboratory values. Forpatients who cannot take oral medicinal product, dimercaprol administered at a dose of 3 mg/kgintramuscularly every 4 hours until any immediately life-threatening toxicity has subsided may beconsidered. Thereafter, penicillamine at a daily dose ≤ 1 g per day may be given. In the presence ofcoagulopathy, 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 isrecommended. For patients with severe, acute arsenic overdose, dialysis should be considered.

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27

The mechanism of action of arsenic trioxide is not completely understood. Arsenic trioxide causesmorphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosisin NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage ordegradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha (PML/RARalpha).

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 andsafety of arsenic trioxide combined with all-trans-retinoic acid (ATRA) with those of

ATRA+chemotherapy (eg, idarubicin and mitoxantrone) (Study APL0406). Patients with newlydiagnosed APL confirmed by the presence of t(15; 17) or PML-RARα by RT-PCR or microspeckled PML nuclear distribution in leukaemic cells were included. No data are available onpatient with variant translocations like t(11;17) (PLZF/RARα). Patients with significantarrhythmias, EKG abnormalities (congenital long QT syndrome, history or presence of significantventricular or atrial tachyarrhythmia, clinically significant resting bradycardia (<50 beats perminute), 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+ arsenictrioxide treatment group received oral ATRA at 45 mg/m2 daily and iv arsenic trioxide at 0.15mg/kg daily until CR. During consolidation, ATRA was given at the same dose for periods of 2weeks on and 2 weeks off for a total of 7 courses, and arsenic trioxide was given at the same dose 5days 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 andoral ATRA at 45 mg/m2 daily until CR. During consolidation, patients received idarubicin at 5mg/m2 on days 1 to 4 and ATRA at 45 mg/m2 daily for 15 days, then iv mitoxantrone at 10 mg/m2on days 1 to 5 and ATRA again at 45 mg/m2 daily for 15 days, and finally a single dose ofidarubicin at 12 mg/m2 and ATRA at 45 mg/m2 daily for 15 days. Each course of consolidation wasinitiated at haematological recovery from the previous course defined as absolute neutrophil count>1.5×109/L and platelets >100×109/L. Patients in the ATRA+chemotherapy treatment group alsoreceived maintenance treatment for up to 2 years, consisting of oral 6-mercaptopurine at 50 mg/m2daily, intramuscular methotrexate at 15 mg/m2 weekly, and ATRA at 45 mg/m2 daily for 15 daysevery 3 months.

The key efficacy results are summarised in table 3 below:

Table 3

Endpoint ATRA + ATRA + Confidence P-value

Arsenic Chemotherapy interval (CI)trioxide (n = 79)(n = 77) [%][%]p<0.001for noninferiority95 % CI for the2-Year event-free difference, 2-2297 86 p = 0.02survival (EFS) percentagefor superiority ofpoints

ATRA+Arsenictrioxide

Hematologiccomplete remission 100 95 p = 0.12(HCR)2-Year overall99 91 p = 0.02survival (OS)2-Year disease-free97 90 p = 0.11survival (DFS)2-Year cumulativeincidence of relapse 1 6 p = 0.24(CIR)

APL = acute promyelocytic leukaemia; ATRA = all-trans-retinoic acid

Relapsed/refractory APL

Arsenic trioxide has been investigated in 52 APL patients, previously treated with an anthracyclineand a retinoid regimen, in two open-label, single-arm, non-comparative studies. One was a singleinvestigator 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 0.06to 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 ofleukaemic cells, up to a maximum of 60 days. Patients with complete remission receivedconsolidation therapy with arsenic trioxide for 25 additional doses over a 5 weeks period.

Consolidation therapy began 6 weeks (range, 3-8) after induction in the single institution study and4 weeks (range, 3-6) in the multicentre study. Complete remission (CR) was defined as the absenceof visible leukaemic cells in the bone marrow and peripheral recovery of platelets and white bloodcells.

Patients in the single centre study had relapsed following 1-6 prior therapy regimens and 2 patientshad relapsed following stem cell transplantation. Patients in the multicentre study had relapsedfollowing 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 themulticentre study was 40 years (age range 5 to 73).

The results are summarised in the table 4 below.

Table 4

Single centre trial Multicentre trial

N=12 N=40

Arsenic trioxide dose, 0.16 (0.06 - 0.20) 0.15mg/kg/day (median, range)

Complete remission 11 (92%) 34 (85%)

Time to bone marrow 32 days 35 daysremission (median)

Time to CR (median) 54 days 59 days18-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. Nochildren 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 patientsin the multicentre study received further maintenance therapy with arsenic trioxide. Three patientsfrom the single institution study and 15 patients from the multicentre study had stem cell transplantsafter completing arsenic trioxide. The Kaplan-Meier median CR duration for the single institutionstudy is 14 months and has not been reached for the multicentre study. At last follow-up, 6 of 12patients in the single institution study were alive with a median follow-up time of 28 months (range25 to 29). In the multicentre study 27 of 40 patients were alive with a median follow-up time of 16months (range 9 to 25). Kaplan-Meier estimates of 18-month survival for each study are shownbelow.

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

Cytogenetics after arsenic trioxide therapy

Table 5

Single centre pilot trial Multicentre trial

N with CR = 11 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/

RAR

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 wassimilar for both genders. There is no experience on the effect of arsenic trioxide on the variant APLcontaining the t(11;17) and t(5;17) chromosomal translocations.

The experience in children is limited. Of 7 patients under 18 years of age (range 5 to 16 years) treatedwith arsenic trioxide at the recommended dose of 0.15 mg/kg/day, 5 patients achieved a completeresponse (see section 4.2).

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

III

The volume of distribution (Vd) for As is large (>400 L) indicating significant distribution into thetissues with negligible protein binding. Vd is also weight dependent, increasing with increasing bodyweight. Total arsenic accumulates mainly in the liver, kidney, and heart and, to a lesser extent, in thelung, hair, and nails.

The metabolism of arsenic trioxide involves oxidation of arsenious acid (AsIII), the active species ofarsenic trioxide, to arsenic acid (AsV), as well as oxidative methylation to monomethylarsonic acid(MMAV) and dimethylarsinic acid (DMAV) by methyltransferases, primarily in the liver. Thepentavalent metabolites, MMAV and DMAV, are slow to appear in plasma (approximately 10-24hours after first administration of arsenic trioxide), but due to their longer half-life, accumulate moreupon multiple dosing than does AsIII. The extent of accumulation of these metabolites is dependenton the dosing regimen. Approximate accumulation ranged from 1.4- to 8-fold following multiple ascompared 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 noinhibitory 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 notexpected to interact with arsenic trioxide.

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. Theplasma concentration of AsIII declines from peak plasma concentration in a biphasic manner with amean 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 rangestudied. The mean estimated terminal elimination half-lives of the metabolites MMAV and DMAVare 32 hours and 70 hours, respectively.

Plasma clearance of AsIII was not altered in patients with mild renal impairment (creatinine clearanceof 50-80 mL/min) or moderate renal impairment (creatinine clearance of 30-49 mL/min). The plasmaclearance 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; theclinical consequence of this is unknown but no increased toxicity was noted.

Pharmacokinetic data from patients with hepatocellular carcinoma having mild to moderate hepaticimpairment indicate that AsIII or AsV do not accumulate following twice-weekly infusions. No cleartrend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed withdecreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC.

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 mannerand is characterized by an initial rapid distribution phase followed by a slower terminal eliminationphase. After administration at 0.15 mg/kg on a daily (n=6) or twice-weekly (n=3) regimen, anapproximate 2-fold accumulation of AsIII was observed as compared to a single infusion. Thisaccumulation was slightly more than expected based on single-dose results.

Limited reproductive toxicity studies of arsenic trioxide in animals indicate embryotoxicity andteratogenicity (neural tube defects, anophthalmia and microphthalmia) at administration of 1-10times the recommended clinical dose (mg/m2). Fertility studies have not been conducted with arsenictrioxide. Arsenic compounds induce chromosomal aberrations and morphological transformations ofmammalian cells in vitro and in vivo. No formal carcinogenicity studies of arsenic trioxide have beenperformed. However, arsenic trioxide and other inorganic arsenic compounds are recognised ashuman carcinogens.

Sodium hydroxide

Hydrochloric acid, concentrated (for pH adjustment)

Water for injections

In the absence of incompatibility studies, this medicinal product must not be mixed with othermedicinal products except those mentioned in section 6.6.

Unopened vial3 years

Once opened the product should be used immediately.

Chemical and physical in-use stability has been demonstrated for 168 hours at 25 °C and at 2°C to8°C. From a microbiological point of view, the product must be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlledand validated aseptic conditions.

This medicinal product does not require any special storage conditions.

For storage conditions after dilution or first opening of the medicinal product, see section 6.3.

Type I transparent colorless glass vial sealed with a silicon-oil free, elastomer type, grey rubberstopper made of bromobutyl and aluminium seal with a plastic flip off cap containing 10 ml ofconcentrate.

Each pack contains 1, 5 or 10 vials.

Not all pack sizes may be marketed.

Preparation of Arsenic trioxide Accord

Aseptic technique must be strictly observed throughout handling of Arsenic trioxide Accord since nopreservative is present.

Arsenic trioxide Accord must be diluted with 100 to 250 ml of glucose 50 mg/ml (5%) solution forinjection or sodium chloride 9 mg/ml (0.9%) solution for injection immediately after withdrawal fromthe vial. PVC free plastic bags should be used. It is for single use only, and any unused portions ofeach vial must be discarded properly. Do not save any unused portions for later administration.

Arsenic trioxide Accord must not be mixed with or concomitantly administered in the sameintravenous line with other medicinal products.

Arsenic trioxide Accord must be administered intravenously over 1-2 hours. The infusion durationmay be extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is notrequired.

The diluted solution must be clear and colourless. All parenteral solutions must be inspected visuallyfor particulate matter and discoloration prior to administration. Do not use the preparation if foreignparticulate matter is present.

Procedure for proper disposal

Any unused medicinal product, any items that come into contact with the product or waste materialmust be disposed of in accordance with local requirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona S/N,

Edifici Est, 6a planta,08039 Barcelona,

Spain

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

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

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

Date of first authorisation: 14th November 2019

Detailed information on this medicinal product is available on the website of the European Medicines

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