Arsenic trioxide is indicated for induction of remission and consolidation in adult patients with: newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (APL) (white blood cell count ≤ 10 x 103/µl) in combination with all-trans-retinoic acid (ATRA), relapsed/refractory acute promyelocytic leukaemia (APL) (prior therapy should have included a retinoid and chemothe

ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion: Koncentrat do sporządzania roztworu do infuzji 1 mg/ml

Summary of the safety profile Adverse reactions associated with CTC grade 3 and 4 occurred in clinical trials in 37% of patients with refractory/relapsed APL. The most commonly reported reactions were: hyperglycaemia, hypokalaemia, neutropenia and elevated alanine aminotransferase (ALT) values. Leukocytosis occurred in 50% of patients with refractory/relapsed APL; it was determin

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

ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion

Q: Warnings?

Patients with clinically unstable APL are at particular risk and will require more frequent monitoring of electrolytes and blood glucose levels, as well as more frequent haematological, renal, coagulation and liver function tests. Leukocyte activation syndrome (APL differentiation syndrome) A total of 27% of patients with relapsed/refractory APL treated with arsenic trioxide reported symptoms simi

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ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion — Description, Dosage, Side Effects | PillsCard

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27 Mechanism of action The mechanism of action of arsenic trioxide is not completely understood.‍‍‍‍‍‍‍‍‍‍‍‍‍ Arsenic trioxide causes changes in morphology 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 promyelocytic leukaemia/retinoic acid receptor alpha (PML/RAR alpha) fusion protein. Clinical efficacy and safety Newly diagnosed APL patients who are not at high risk Arsenic trioxide was studied in 77 newly diagnosed low-to-intermediate risk APL patients in a controlled, randomised, phase 3 non-inferiority clinical trial comparing the efficacy and safety of arsenic trioxide in combination with all-trans-retinoic acid (ATRA) with the efficacy and safety of ATRA in combination with chemotherapy (e.g. idarubicin and mitoxantrone) (study APL0406). Patients enrolled in the study had newly diagnosed APL confirmed by the presence of t(15;17), PML-RARα by RT-PCR or microgranular distribution of PML in the cell nucleus in leukaemic cells. No data are available on patients with variant translocations, such as t(11;17) (PLZF/RARα). Patients with significant arrhythmias, ECG abnormalities (congenital long QT syndrome, significant ventricular or atrial tachycardia current or history of, clinically significant resting bradycardia (< 50 beats per minute), QTc > 450 ms on screening ECG, right bundle branch block plus left anterior hemiblock, bifascicular block) or neuropathy were excluded from the study. Patients in the ATRA + arsenic trioxide treatment group received oral ATRA at a dose of 45 mg/m2 daily and intravenous arsenic trioxide at a dose of 0.15 mg/kg daily until complete remission was achieved. During consolidation, ATRA was administered at the same dose for 2 weeks with a 2-week break, for a total of 7 cycles. Arsenic trioxide was administered at the same dose 5 days per week for 4 weeks with a 4-week break, for a total of 4 cycles. Patients in the ATRA and chemotherapy treatment group received intravenous idarubicin at a dose of 12 mg/m2 on days 2, 4, 6 and 8 and oral ATRA at a dose of 45 mg/m2 daily until complete remission was achieved. During consolidation, patients received idarubicin at a dose of 5 mg/m2 on days 1 to 4 and ATRA at a dose of 45 mg/m2 daily for 15 days. Then they received intravenous mitoxantrone at a dose of 10 mg/m2 on days 1 to 5 and again ATRA at a dose of 45 mg/m2 daily for 15 days, and finally a single dose of idarubicin 12 mg/m2 and ATRA at a dose of 45 mg/m2 daily for 15 days. Each consolidation cycle was initiated upon haematological recovery from the previous cycle, defined as an absolute neutrophil count > 1.5×109/l and platelets > 100×109/l. Patients in the ATRA + chemotherapy treatment group also underwent maintenance therapy for up to 2 years, consisting of oral mercaptopurine at a dose of 50 mg/m2 daily, intramuscular methotrexate at a dose of 15 mg/m2 weekly and ATRA at a dose of 45 mg/m2 daily for 15 days once every 3 months. 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 p < 0.001 95% CI for for non-inferiority 2-year event-free survival (EFS) 97 86 difference, 2–22 percentage p = 0.02 points for superiority ATRA + arsenic trioxide Complete haematological remission (CHR) 100 95 p = 0.12 2-year overall survival (OS) 99 91 p = 0.02 2-year disease-free survival (DFS) 97 90 p = 0.11 2-year cumulative incidence of relapse (CIR) 1 6 p = 0.24 APL = acute promyelocytic leukaemia; ATRA = all-trans-retinoic acid Relapsed/refractory APL Arsenic trioxide was studied in 52 APL patients who were previously treated with an anthracycline and retinoids, in two open-label, single-arm, non-comparative studies. One was a single-investigator clinical trial (n = 12) and the other was a multicentre study conducted at nine institutions (n = 40). Patients in the first study received a median dose of arsenic trioxide of 0.16 mg/kg/day (range 0.06 to 0.20 mg/kg/day) and patients enrolled in the multicentre study received a fixed dose of 0.15 mg/kg/day. Arsenic trioxide was administered intravenously over one to two hours until the bone marrow was cleared of leukaemic cells, but for no longer than 60 days. Patients who achieved complete remission received an additional 25 doses as consolidation therapy with arsenic trioxide over a five-week period. Consolidation therapy was initiated 6 weeks (range 3–8) after induction in the single-centre study and 4 weeks (range 3–6) after induction in the multicentre study. Complete remission 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 after 1–6 prior treatment regimens and two patients had relapsed after stem cell transplantation. Patients in the multicentre study had relapsed after 1–4 prior treatment regimens and 5 patients had relapsed after stem cell transplantation. The median age in the single-centre study was 33 years (age range 9 to 75 years). The median age in the multicentre study was 40 years (age range 5 to 73 years). A summary of results is provided in Table 4 below: Table 4 Single-centre study n = 12 Multicentre study n = 40 Arsenic trioxide dose in mg/kg/day (median, range) 0.16 (0.06 – 0.20) 0.15 Complete remission 11 (92%) 34 (85%) Time to bone marrow remission (median) 32 days 35 days Time to complete remission (median) 54 days 59 days 18-month survival 67% 66% Two paediatric patients (under 18 years of age) were enrolled in the single-centre study, both achieved complete remission. Five paediatric patients (under 18 years of age) were enrolled in the multicentre study, three of whom achieved complete remission. No children under five years of age were treated. As subsequent treatment after consolidation, seven patients in the single-centre study and 18 patients in the multicentre study received additional maintenance therapy with arsenic trioxide. Three patients from the single-centre study and 15 patients from the multicentre study underwent stem cell transplantation after completion of arsenic trioxide treatment. The Kaplan-Meier median duration of complete remission in the single-centre study was 14 months; in the multicentre study it was not reached. At last follow-up, six of 12 patients from the single-centre 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 both studies are shown below. 100% 80% 60% 40% 20% Single Center Multicenter Study At Risk 12 40 Deaths 6 13 18-Month 67% 66% 0% 0 6 12 18 24 30 36 Months Legend: Single center – Single centre Multicenter Study – Multicentre study At risk – At risk Deaths – Deaths 18-month – 18 months Months – Months Cytogenetic confirmation of conversion to normal genotype and detection of PML/RARα conversion to normal by reverse transcriptase-polymerase chain reaction (RT-PCR) are shown in Table 5 below. Cytogenetics after arsenic trioxide treatment Table 5 Pilot single-centre study n with complete remission = 11 Multicentre study n with complete remission = 34 Conventional cytogenetics [t(15;17)] Not performed 8 (73%) 31 (91%) Performed 1 (9%) 0% Non-evaluable 2 (18%) 3 (9%) RT-PCR for PML/ RARα Negative 8 (73%) 27 (79%) Positive 3 (27%) 4 (12%) Non-evaluable 0 3 (9%) Responses were observed in all age groups studied, ranging from 6 to 75 years. The response rate was similar in both sexes. There is no experience with the effects of arsenic trioxide in variant APL containing chromosomal translocations t(11;17) and t(5;17). Paediatric population 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).

⚠️ Warnings

Patients with clinically unstable APL are at particular risk and will require more frequent monitoring of electrolytes and blood glucose levels, as well as more frequent haematological, renal, coagulation and liver function tests. Leukocyte activation syndrome (APL differentiation syndrome) A total of 27% of patients with relapsed/refractory APL treated with arsenic trioxide reported symptoms similar to a syndrome called RA-acute promyelocytic leukaemia (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 identified in 19% of cases, including 5 severe cases. At the first signs that could suggest the development of this syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultation findings or abnormalities visible on chest X-rays), arsenic trioxide treatment must be temporarily stopped and high-dose steroid therapy must be immediately initiated (dexamethasone 10 mg intravenously twice daily), regardless of the white blood cell count; treatment must continue for a minimum of three days or longer, until signs and symptoms have resolved. Concomitant treatment with diuretics is also recommended in clinically indicated cases/as needed. In most patients, it is not necessary to permanently discontinue arsenic trioxide during treatment of APL differentiation syndrome. Once signs and symptoms have resolved, arsenic trioxide treatment may be resumed at a dose that corresponds to 50% of the previous dose for the first 7 days. Thereafter, if the previous toxicity does not recur, arsenic trioxide treatment may be resumed at the full dose. If symptoms reappear, the arsenic trioxide dose must be reduced to the previous level. To prevent the development of APL differentiation syndrome during induction therapy, prednisone (0.5 mg/kg body weight daily throughout the induction treatment) may be administered to APL patients from day 1 of arsenic trioxide administration until the end of induction therapy. It is recommended not to combine steroid therapy with chemotherapy, as there is no experience with the administration of steroids and chemotherapy during treatment of leukocyte activation syndrome induced by arsenic trioxide. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancies. Monitoring and treatment of these patients should follow the procedure described above. Electrocardiogram (ECG) abnormalities Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT interval prolongation can lead to a ventricular arrhythmia of the torsades de pointes type, which can be fatal. Prior treatment with anthracyclines may increase the risk of QT prolongation. The risk of torsades de pointes is related to the extent of QT interval prolongation, concomitant administration of medicinal products that prolong the QT interval (such as class Ia and III antiarrhythmics, e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazine), antidepressants (e.g. amitriptyline), certain macrolides (e.g. erythromycin), certain antihistamines (e.g. terfenadine and astemizole), certain quinolone antibiotics (e.g. sparfloxacin) and other individual medicinal products that prolong the QT interval (e.g. cisapride), a history of torsades de pointes, pre-existing QT prolongation, congestive heart failure, administration of potassium-depleting diuretics, amphotericin B, or other conditions resulting in hypokalaemia or hypomagnesaemia. In clinical trials conducted in relapsed/refractory patients, at least one QTc prolongation exceeding 500 ms occurred in 40% of patients treated with arsenic trioxide. QTc prolongation was observed between the first and fifth week after infusion of arsenic trioxide, with return to baseline within eight weeks after infusion of arsenic trioxide. In one patient (who was concomitantly receiving several medicinal products including amphotericin B), asymptomatic torsades de pointes occurred during induction therapy for relapsed APL with arsenic trioxide. In newly diagnosed APL, when arsenic trioxide was administered in combination with ATRA (see section 4.8), 15.6% of patients showed QTc interval prolongation. In one newly diagnosed patient, induction therapy was discontinued due to severe QTc interval prolongation and electrolyte abnormalities on day 3 of induction therapy. Recommendations for ECG and electrolyte monitoring A 12-lead ECG must be performed and serum electrolyte levels (potassium, calcium and magnesium) and creatinine must be evaluated before starting arsenic trioxide treatment; existing electrolyte abnormalities must be corrected and, where possible, medicinal products that cause QT prolongation should be discontinued. Cardiac function in patients with risk factors for QTc prolongation or risk factors for torsades de pointes should be continuously monitored (using ECG). If the QTc interval is longer than 500 ms, corrective measures must be completed and the QTc interval must be re-assessed by serial ECGs; if possible, specialist advice may be sought before considering administration of arsenic trioxide. During arsenic trioxide treatment, potassium concentrations must be maintained above 4 mEq/l and magnesium concentrations above 1.8 mg/dl. Patients whose absolute QT interval exceeds 500 ms must be re-assessed and immediate action must be taken to correct concomitant risk factors, if present, while the risks and benefits of continuing or discontinuing arsenic trioxide treatment must be considered. If syncope, rapid or irregular heartbeat occurs, the patient must be hospitalised and continuously monitored, serum electrolytes must be evaluated, and arsenic trioxide treatment must be temporarily interrupted until the QTc interval decreases below 460 ms, electrolyte abnormalities are corrected, and syncope and irregular heartbeat have resolved. After recovery, treatment should be resumed at a dose corresponding to 50% of the previous daily dose. If QTc prolongation does not recur within 7 days of resuming treatment at the reduced dose, arsenic trioxide treatment may be resumed in the second week at a dose of 0.11 mg/kg body weight per day. If no prolongation occurs, the daily dose may be increased back to 100% of the original dose. Data on the effect of arsenic trioxide on the QTc interval during infusion are not available. Electrocardiograms must be performed twice weekly during induction and consolidation; more frequently in clinically unstable patients. Hepatotoxicity (grade 3 or higher) In newly diagnosed low-to-intermediate risk APL patients, grade 3 or 4 hepatotoxic effects occurred in 63.2% of patients during induction or consolidation therapy with arsenic trioxide in combination with ATRA (see section 4.8). However, the toxic effects resolved upon temporary discontinuation of arsenic trioxide, ATRA or both. Arsenic trioxide treatment must be discontinued before the scheduled end of treatment whenever grade 3 or higher hepatotoxicity is identified based on the National Cancer Institute Common Toxicity Criteria. Once bilirubin, SGOT and/or alkaline phosphatase concentrations decrease below four times the upper limit of normal, arsenic trioxide treatment should be resumed at a dose corresponding to 50% of the previous dose for the first 7 days. Thereafter, if the previous toxicity does not recur, arsenic trioxide treatment may be resumed at the full dose. If hepatotoxicity recurs, arsenic trioxide treatment must be permanently discontinued. Dose adjustment Arsenic trioxide treatment must be temporarily discontinued before the end of the treatment cycle whenever grade 3 or higher toxicity is observed according to the National Cancer Institute Common Toxicity Criteria and the toxicity is considered possibly related to arsenic trioxide therapy (see section 4.2). Laboratory tests Serum electrolyte and blood glucose levels, haematological and renal parameters, coagulation parameters and liver function tests must be monitored at least twice weekly during the induction phase, more frequently in clinically unstable patients, and at least once weekly during the consolidation phase. Renal impairment Since no data are available for all groups of renal impairment, caution is recommended when using arsenic trioxide in patients with renal impairment. Experience in patients with severe renal impairment is insufficient to determine whether dose adjustment is necessary. The use of arsenic trioxide in patients undergoing dialysis has not been studied. Hepatic impairment Since no data are available for all groups of hepatic impairment and hepatotoxic effects may occur with arsenic trioxide treatment, caution should be exercised when using arsenic trioxide in patients with hepatic impairment (see section 4.4 on hepatotoxicity and section 4.8). Experience in patients with severe hepatic impairment is insufficient to determine whether dose adjustment is necessary. Elderly population There are limited clinical data on the use of arsenic trioxide in elderly patients. Caution should be exercised in these patients. Hyperleukocytosis Treatment with arsenic trioxide in some patients with relapsed/refractory APL was associated with the development of hyperleukocytosis (≥ 10 x 103/μl). There appeared to be no correlation between baseline white blood cell count and the development of hyperleukocytosis, nor between the baseline white blood cell count and the peak white blood cell count. Hyperleukocytosis was never treated with additional chemotherapy and resolved with continued arsenic trioxide therapy. White blood cell counts during consolidation were not as high as during induction therapy and were within 10 x 103/μl, with the exception of one patient whose white blood cell count during consolidation was 22 x 103/μl. In twenty patients with relapsed/refractory APL (50%), leukocytosis occurred, but in all of these patients white blood cell counts decreased or normalised by the time bone marrow remission was achieved, and cytotoxic chemotherapy or leukapheresis was not required. In 35 of 74 (47%) newly diagnosed low-to-intermediate risk APL patients, leukocytosis developed during induction therapy (see section 4.8). However, all cases were successfully treated with hydroxycarbamide. In patients with newly diagnosed relapsed/refractory APL who develop chronic leukocytosis after starting treatment, hydroxycarbamide should be administered. Hydroxycarbamide at the appropriate dose should be continued to maintain the white blood cell count ≤ 10 x 103/μl, and then the dose should be gradually tapered. Table 1 Recommendations for initiating hydroxycarbamide treatment White blood cell count Hydroxycarbamide 10–50 x 103/µl 500 mg four times daily > 50 x 103/µl 1,000 mg four times daily Development of secondary primary malignancies The active substance of Arsenic trioxide Accord, arsenic trioxide, is a human carcinogen. Monitor patients for the development of secondary primary malignancies. Encephalopathy Cases of encephalopathy have been reported during treatment with arsenic trioxide. In patients with vitamin B1 deficiency, Wernicke's encephalopathy has been reported following treatment with arsenic trioxide. After initiation of arsenic trioxide, patients at risk of vitamin B1 deficiency should be carefully monitored for signs and symptoms of encephalopathy. Some cases resolved after administration of vitamin B1. Excipient with known effect This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 'sodium-free'.

ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion

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