TRISENOX 2mg / ml perfusive solution concentrate medication leaflet

TRISENOX 1 mg/ml concentrate for solution for infusion

TRISENOX 2 mg/ml concentrate for solution for infusion

TRISENOX 1 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 1 mg of arsenic trioxide.

Each ampoule of 10 ml contains 10 mg of arsenic trioxide.

TRISENOX 2 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 2 mg of arsenic trioxide.

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

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless, aqueous solution.

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

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

* Relapsed/refractory acute promyelocytic leukaemia (APL) (previous treatment should haveincluded 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.

TRISENOX 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

TRISENOX 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

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

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

Relapsed/refractory acute promyelocytic leukaemia (APL)

Induction treatment schedule

TRISENOX must be administered intravenously at a fixed dose of 0.15 mg/kg/day given daily untilcomplete remission is achieved (less than 5 % blasts present in cellular bone marrow with no evidenceof leukaemic cells). If complete remission has not occurred by day 50, dosing must be discontinued.

Consolidation schedule

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

Dose delay, modification and reinitiation

Treatment with TRISENOX must be temporarily interrupted before the scheduled end of therapy atany time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteriais observed and judged to be possibly related to TRISENOX treatment. Patients who experience suchreactions that are considered TRISENOX related must resume treatment only after resolution of thetoxic event or after recovery to baseline status of the abnormality that prompted the interruption. Insuch cases, treatment must resume at 50 % of the preceding daily dose. If the toxic event does notrecur within 7 days of restarting treatment at the reduced dose, the daily dose can be escalated back to100 % of the original dose. Patients who experience a recurrence of toxicity must be removed fromtreatment.

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 TRISENOX, caution is advised in the use of TRISENOX in patients withhepatic 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

TRISENOX in patients with renal impairment.

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

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

TRISENOX 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 promyelocytic leukaemia(RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain,pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis. This syndromecan 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 firstsigns that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormalchest auscultatory findings or radiographic abnormalities), treatment with TRISENOX must betemporarily 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 orlonger until signs and symptoms have abated. If clinically justified/required, concomitant diuretictherapy is also recommended. The majority of patients do not require permanent termination of

TRISENOX therapy during treatment of the APL differentiation syndrome. As soon as signs andsymptoms have subsided, treatment with TRISENOX can be resumed at 50 % of the previous doseduring the first 7 days. Thereafter, in the absence of worsening of the previous toxicity, TRISENOXmight be resumed at full dosage. In the case of the reappearance of symptoms TRISENOX should bereduced to the previous dosage. In order to prevent the development of the APL differentiationsyndrome during induction treatment, prednisone (0.5 mg/kg body weight per day throughoutinduction treatment) may be administered from day 1 of TRISENOX application to the end ofinduction therapy in APL patients. It is recommended that chemotherapy not be added to treatmentwith steroids since there is no experience with administration of both steroids and chemotherapyduring treatment of the leukocyte activation syndrome due to TRISENOX. Post-marketing experiencesuggests that a similar syndrome may occur in patients with other types of malignancy. Monitoringand management for these patients should 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. Previoustreatment with anthracyclines may increase the risk of QT prolongation. The risk of torsade de pointesis related to the extent of QT prolongation, concomitant administration of QT prolonging medicinalproducts (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 inhypokalaemia or hypomagnesaemia. In clinical trials, in the relapsed/refractory setting, 40 % ofpatients treated with TRISENOX experienced at least one QT corrected (QTc) interval prolongationgreater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after

TRISENOX infusion, and then returned to baseline by the end of 8 weeks after TRISENOX infusion.

One patient (receiving multiple, concomitant medicinal products, including amphotericin B) hadasymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide. Innewly diagnosed APL patients 15.6 % showed QTc prolongation with arsenic trioxide in combinationwith ATRA (see section 4.8). In one newly diagnosed patient induction treatment was terminatedbecause of severe prolongation of the QTc interval and electrolyte abnormalities on day 3 of inductiontreatment.

ECG and electrolyte monitoring recommendations

Prior to initiating therapy with TRISENOX, a 12-lead ECG must be performed and serum electrolytes(potassium, calcium, and magnesium) and creatinine must be assessed; pre-existing electrolyteabnormalities must be corrected and, if possible, medicinal products that are known to prolong the QTinterval must be discontinued. Patients with risk factors of QTc prolongation or risk factors of torsadede pointes should be monitored with continuous cardiac monitoring (ECG). For QTc greater than500 msec, corrective measures must be completed and the QTc reassessed with serial ECGs and, ifavailable, a specialist advice could be sought prior to considering using TRISENOX. During therapywith TRISENOX, potassium concentrations must be kept above 4 mEq/l and magnesiumconcentrations 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 riskfactors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy must beconsidered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised andmonitored continuously, serum electrolytes must be assessed, TRISENOX 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 TRISENOX 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 4 hepatictoxic 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 eitherarsenic trioxide, ATRA or both. Treatment with TRISENOX must be discontinued before thescheduled 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 alkalinephosphatase are decreased to below 4 times the normal upper level, treatment with TRISENOX shouldbe resumed at 50 % of the previous dose during the first 7 days. Thereafter, in absence of worsening ofthe previous toxicity, TRISENOX should be resumed at full dosage. In case of reappearance ofhepatotoxicity, TRISENOX must be permanently discontinued.

Dose delay and modification

Treatment with TRISENOX must be temporarily interrupted before the scheduled end of therapy atany time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteriais observed and judged to be possibly related to TRISENOX 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 of

TRISENOX in patients with renal impairment. The experience in patients with severe renalimpairment is insufficient to determine if dose adjustment is required.

The use of TRISENOX 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 TRISENOX in patients withhepatic impairment (see section 4.4 on hepatotoxicity and section 4.8). The experience in patients withsevere hepatic impairment is insufficient to determine if dose adjustment is required.

There is limited clinical data on the use of TRISENOX in the elderly population. Caution is needed inthese patients.

Hyperleucocytosis

Treatment with arsenic trioxide has been associated with the development of hyperleucocytosis(≥ 10 x 103/μl) in some relapsed/refractory APL patients. There did not appear to be a relationshipbetween baseline white blood cell (WBC) counts and development of hyperleucocytosis nor did thereappear to be a correlation between baseline WBC count and peak WBC counts. Hyperleucocytosiswas never treated with additional chemotherapy and resolved on continuation of TRISENOX. WBCcounts 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. Twentyrelapsed/refractory APL patients (50 %) experienced leucocytosis; however, in all these patients, the

WBC count was declining or had normalized by the time of bone marrow remission and cytotoxicchemotherapy or leucopheresis was not required. In newly diagnosed patients with low to intermediaterisk APL leucocytosis developed during induction therapy in 35 of 74 (47 %) patients (seesection 4.8). However all cases were successfully 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 Hydroxyurea10-50 x 103/µl 500 mg four times a day> 50 x 103/µl 1000 mg four times a day

Development of second primary malignancies

The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for thedevelopment 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 TRISENOX 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 TRISENOX is co-administeredwith other medicinal products known to cause QT/QTc interval prolongation such as macrolideantibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalaemia orhypomagnesaemia. Additional information about QT prolonging medicinal agents, is provided insection 4.4.

Medicinal products known to cause hepatotoxic effects

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

TRISENOX is co-administered with other medicinal products known to cause hepatotoxic effects (seesection 4.4 and 4.8).

Other antileukaemic medicinal products

The influence of TRISENOX on the efficacy of other antileukaemic medicinal products is unknown.

Due to the genotoxic risk of arsenic compounds (see section 5.3), women of childbearing potentialmust use effective contraceptive measures during treatment with TRISENOX and for 6 monthsfollowing completion of treatment.

Men should use effective contraceptive measures and be advised to not father a child while receiving

TRISENOX 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 TRISENOX.

If this medicinal product is used during pregnancy or if the patient becomes pregnant while taking thisproduct, the patient must be informed of the potential harm to the foetus.

Arsenic is excreted in human milk. Because of the potential for serious adverse reactions inbreast-feeding infants and children from TRISENOX, 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 TRISENOX.

TRISENOX 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 APL patientsin clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia,neutropenia, and increased alanine amino transferase (ALT). Leucocytosis occurred in 50 % ofpatients 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. Patients tendedto tolerate consolidation and maintenance treatment with less toxicity than in induction. This isprobably due to the confounding of adverse events by the uncontrolled disease process early on in thetreatment course and the myriad concomitant medicinal products required to control symptoms andmorbidity.

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 TRISENOX clinical trials in 52 patients with refractory/relapsed APL.

Frequencies are defined as: (very common ≥ 1/10), (common ≥ 1/100 to < 1/10),(uncommon ≥ 1/1,000 to < 1/100), not known (cannot be estimated from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2

All grades Grades ≥ 3

Herpes zoster Common Not known

Sepsis Not known Not known

Pneumonia Not known Not known

Febrile neutropenia Common Common

Leucocytosis Common Common

Neutropenia Common Common

Pancytopenia Common Common

Thrombocytopenia Common Common

Anaemia Common Not known

Leukopenia Not known Not known

Lymphopenia Not known Not known

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

Confusional state Not known Not known

Paraesthesia Very Common Common

Dizziness Very Common Not known

Headache Very Common Not known

Convulsion Common Not known

All grades Grades ≥ 3

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 haemorrhage Common Common

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

Fatigue Very Common Not known

Oedema Very Common Not known

Chest pain Common Common

Chills Common Not known

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 200patients who received TRISENOX consolidation cycles (cycle 1 and cycle 2) versus none in the controlarm.

During TRISENOX treatment, 14 of the 52 patients in the APL studies in the relapsed setting had oneor more symptoms of APL differentiation syndrome, characterised by fever, dyspnoea, weight gain,pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis (see section4.4). Twenty-seven patients had leucocytosis (WBC ≥ 10 x 103/µl) during induction, 4 of whom hadvalues above 100,000/µl. Baseline white blood cell (WBC) counts did not correlate with developmentof leucocytosis on study, and WBC counts during consolidation therapy were not as high as duringinduction. In these studies, leucocytosis was not treated with chemotherapeutic medicinal products.

Medicinal products that are used to lower the white blood cell count often exacerbate the toxicitiesassociated with leucocytosis, and no standard approach has proven effective. One patient treated undera compassionate use program died from cerebral infarct due to leucocytosis, following treatment withchemotherapeutic medicinal products to lower WBC count. Observation is the recommended approachwith 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 was observedin 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 TRISENOX.

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 APL witharsenic 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 known effectof environmental arsenic. Only 2 relapsed/refractory APL patients discontinued treatment early due tothis adverse event and one went on to receive additional TRISENOX on a subsequent protocol.

Forty-four per cent of relapsed/refractory APL patients experienced symptoms that could be associatedwith neuropathy; most were mild to moderate and were reversible upon cessation of treatment with

TRISENOX.

Hepatotoxicity (grade 3-4)

In newly diagnosed patients with low to intermediate risk APL 63.2 % developed grade 3 or 4 hepatictoxic effects during induction or consolidation treatment with TRISENOX in combination with

ATRA. However, toxic effects resolved with temporary discontinuation of either TRISENOX, ATRAor 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 TRISENOX 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, TRISENOX 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. For patientswho 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 TRISENOX is not completely understood. Arsenic trioxide causesmorphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in

NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage ordegradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha(PML/RAR alpha).

Newly diagnosed non high risk APL patients

TRISENOX has been investigated in 77 newly diagnosed patients with low to intermediate risk APL,in a controlled, randomized, non-inferiority Phase 3 clinical study comparing the efficacy and safety of

TRISENOX combined with all-trans-retinoic acid (ATRA) with those of ATRA + chemotherapy (eg,idarubicin and mitoxantrone) (Study APL0406). Patients with newly diagnosed APL confirmed by thepresence of t(15; 17) or PML-RARα by RT-PCR or micro speckled PML nuclear distribution inleukaemic cells were included. No data are available on patient with variant translocations liket(11;17) (PLZF/RARα). Patients with significant arrhythmias, EKG abnormalities (congenital long QTsyndrome, history or presence of significant ventricular or atrial tachyarrhythmia, clinically significantresting bradycardia (< 50 beats per minute), QTc > 450 msec on screening EKG, right bundle branchblock plus left anterior hemiblock, bifascicular block) or neuropathy were excluded from the study.

Patients in the ATRA + TRISENOX treatment group received oral ATRA at 45 mg/m2 daily and IV

TRISENOX at 0.15 mg/kg daily until CR. During consolidation, ATRA was given at the same dosefor periods of 2 weeks on and 2 weeks off for a total of 7 courses, and TRISENOX was given at thesame 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 andoral ATRA at 45 mg/m2 daily until CR. During consolidation, patients received idarubicin at 5 mg/m2on days 1 to 4 and ATRA at 45 mg/m2 daily for 15 days, then IV mitoxantrone at 10 mg/m2 on days 1to 5 and ATRA again at 45 mg/m2 daily for 15 days, and finally a single dose of idarubicin at12 mg/m2 and ATRA at 45 mg/m2 daily for 15 days. Each course of consolidation was initiated athaematological recovery from the previous course defined as absolute neutrophil count > 1.5 × 109/land platelets > 100 × 109/l. Patients in the ATRA + chemotherapy treatment group also receivedmaintenance treatment for up to 2 years, consisting of oral 6-mercaptopurine at 50 mg/m2 daily,intramuscular methotrexate at 15 mg/m2 weekly, and ATRA at 45 mg/m2 daily for 15 days every3 months.

The key efficacy results are summarised in table 3 below:

Table 3

Endpoint ATRA + ATRA + Confidence P-value

TRISENOX Chemotherapy interval (CI)(n = 77) (n = 79)[%] [%]95 % CI for p < 0.0012-Year event-free the difference, for non-inferioritysurvival (EFS) 97 86 2-22percentage p = 0.02points for superiority of

ATRA + TRISENOX

Haematologiccomplete remission 100 95 p = 0.12(HCR)2-Year overallsurvival (OS) 99 91 p = 0.022-Year disease-freesurvival (DFS) 97 90 p = 0.112-Year cumulativeincidence of relapse 1 6 p = 0.24(CIR)

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

Relapsed/refractory APL

TRISENOX has been investigated in 52 APL patients, previously treated with an anthracycline and aretinoid 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). Patientsin the first study received a median dose of 0.16 mg/kg/day of TRISENOX (range 0.06 to0.20 mg/kg/day) and patients in the multicentre study received a fixed dose of 0.15 mg/kg/day.

TRISENOX was administered intravenously over 1 to 2 hours until the bone marrow was free ofleukaemic cells, up to a maximum of 60 days. Patients with complete remission received consolidationtherapy with TRISENOX for 25 additional doses over a 5 week period. Consolidation therapy began6 weeks (range, 3-8) after induction in the single institution study and 4 weeks (range, 3-6) in themulticentre study. Complete remission (CR) was defined as the absence of visible leukaemic cells inthe 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 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

TRISENOX dose, mg/kg/day 0.16 (0.06 - 0.20) 0.15(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 patients inthe multicentre study received further maintenance therapy with TRISENOX. Three patients from thesingle institution study and 15 patients from the multicentre study had stem cell transplants aftercompleting TRISENOX. The Kaplan-Meier median CR duration for the single institution study is 14months and has not been reached for the multicentre study. At last follow-up, 6 of 12 patients in thesingle institution study were alive with a median follow-up time of 28 months (range 25 to 29). In themulticentre study 27 of 40 patients were alive with a median follow-up time of 16 months (range9 to 25). Kaplan-Meier estimates of 18-month survival for each study are shown below.

100%80%60%40%

At Risk Deaths 18-Month20% Single Center 12 6 67%

Multicenter Study 40 13 66%0%0 6 12 18 24 30 36

Months

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

Cytogenetics after TRISENOX 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/

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 wassimilar for both genders. There is no experience on the effect of TRISENOX 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 TRISENOX 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.

The volume of distribution (Vd) for AsIII 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 10-24 hoursafter first administration of arsenic trioxide), but due to their longer half-life, accumulate more uponmultiple dosing than does AsIII. The extent of accumulation of these metabolites is dependent on thedosing 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 TRISENOX.

Approximately 15 % of the administered TRISENOX dose is excreted in the urine as unchanged AsIII.

The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine. The plasmaconcentration of AsIII declines from peak plasma concentration in a biphasic manner with a meanterminal elimination half-life of 10 to 14 hours. The total clearance of AsIII over the single-dose rangeof 7-32 mg (administered as 0.15 mg/kg) is 49 l/h and the renal clearance is 9 l/h. Clearance is notdependent on the weight of the subject or the dose administered over the dose range studied. The meanestimated terminal elimination half-lives of the metabolites MMAV and DMAV are 32 hours and70 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 1-10 timesthe recommended clinical dose (mg/m2). Fertility studies have not been conducted with TRISENOX.

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 as humancarcinogens.

Sodium hydroxide

Hydrochloric acid (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.

TRISENOX 1 mg/ml concentrate for solution for infusion4 years.

TRISENOX 2 mg/ml concentrate for solution for infusion4 years.

After dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at15-30 °C and 72 hours at refrigerated (2-8 °C) temperatures. From a microbiological point of view, theproduct must be used immediately. If not used immediately, in-use storage times and conditions priorto 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.

This medicinal product does not require any special storage conditions.

For storage conditions after dilution of the medicinal products, see section 6.3.

TRISENOX 1 mg/ml concentrate for solution for infusion

Type I borosilicate glass ampoule containing 10 ml of concentrate.

Each pack contains 10 ampoules.

TRISENOX 2 mg/ml concentrate for solution for infusion6 ml concentrate in a clear, Type I borosilicate glass vial, sheathed in a protective plastic sleeve, with achlorobutyl rubber stopper (FluroTec coated plug) and an aluminium crimp cap with a plastic flip-topbutton.

Each pack contains 10 vials.

Preparation of TRISENOX

Aseptic technique must be strictly observed throughout handling of TRISENOX since no preservativeis present.

TRISENOX must be diluted with 100 to 250 ml of glucose 50 mg/ml (5 %) solution for injection orsodium chloride 9 mg/ml (0.9 %) solution for injection immediately after withdrawal from theampoule or vial.

TRISENOX must not be mixed with or concomitantly administered in the same intravenous line withother medicinal products.

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

TRISENOX is for single use only and any unused portions of each ampoule or of each vial must bediscarded 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 materialmust be disposed of in accordance with local requirements.

Teva B.V.

Swensweg 52031 GA Haarlem

Netherlands

TRISENOX 1 mg/ml concentrate for solution for infusion

EU/1/02/204/001

TRISENOX 2 mg/ml concentrate for solution for infusion

EU/1/02/204/002

Date of first authorisation: 05 March 2002

Date of latest renewal: 05 March 2007

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

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