What is the active ingredient in ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion?

Arsenii trioxidum (Arsenii trioxidum)

What are the side effects of ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion?

Summary of the safety profile Adverse reactions of CTC grade 3 and 4 occurred in 37% of patients with refractory/relapsed APL in clinical studies. 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 determined on the basis of haematological assessment. Serious adverse reactions were common (1–10%) in the refractory/re

Does ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion interact with other medications?

No formal assessments of pharmacokinetic interactions between arsenic trioxide and other medicinal products have been conducted. Medicinal products known to cause QT/QTc interval prolongation, hypokalaemia or hypomagnesaemia QT/QTc interval prolongation is expected during treatment with arsenic trioxide; torsades de pointes and complete heart block have also been reported. In patients who are taking or have taken medicinal products known to cause hypokalaemia or hypomagnesaemia

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

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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 to 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 of 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 current or prior history of ventricular or atrial tachycardia, 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/m 2 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 plus chemotherapy treatment group received intravenous idarubicin at a dose of 12 mg/m 2 on days 2, 4, 6 and 8 and oral ATRA at a dose of 45 mg/m 2 daily until complete remission was achieved. During consolidation, patients received idarubicin at a dose of 5 mg/m 2 on days 1 to 4 and ATRA at a dose of 45 mg/m 2 daily for 15 days. They then received intravenous mitoxantrone at a dose of 10 mg/m 2 on days 1 to 5 and again ATRA at a dose of 45 mg/m 2 daily for 15 days, and finally a single dose of idarubicin 12 mg/m 2 and ATRA at a dose of 45 mg/m 2 daily for 15 days. Each consolidation cycle was initiated upon haematological recovery from the previous cycle, defined as absolute neutrophil count > 1.5×10 9 /l and platelets > 100×10 9 /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/m 2 daily, intramuscular methotrexate at a dose of 15 mg/m 2 weekly and ATRA at a dose of 45 mg/m 2 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 patients with APL who had previously been 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 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 clear of leukaemic cells, but for no longer than 60 days. Patients achieving complete remission received an additional 25 doses of arsenic trioxide as consolidation therapy 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 the 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 of whom 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 of 28 months (range 25 to 29). In the multicentre study, 27 of 40 patients were alive with a median follow-up 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 Centre 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% 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 observed across all age groups studied, ranging from 6 to 75 years. The response rate was similar for both sexes. There is no experience with the effects of arsenic trioxide in variant APL involving 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 more frequent monitoring of electrolytes and blood glucose levels as well as more frequent haematological, renal, coagulation and hepatic function testing will be required. 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, which is characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis.‍‍‍‍‍‍‍‍‍‍‍‍‍ This syndrome can be fatal. In patients with newly diagnosed APL 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 auscultatory chest findings or abnormalities seen on chest X-rays), arsenic trioxide treatment must be temporarily stopped and high-dose steroid therapy must be initiated immediately (dexamethasone 10 mg intravenously twice daily), regardless of the white blood cell count; treatment must continue for at least three days or longer until signs and symptoms have resolved. In clinically appropriate cases/as needed, concomitant treatment with diuretics is also recommended. In the majority of patients, it is not necessary to permanently discontinue arsenic trioxide during the treatment of APL differentiation syndrome. Once signs and symptoms have resolved, arsenic trioxide therapy may be restarted at a dose corresponding to 50% of the previous dose for the first 7 days. Thereafter, if prior toxicity does not worsen again, arsenic trioxide therapy may be resumed at full dose. If symptoms recur, arsenic trioxide dosing must be reduced to the previous level. To prevent APL differentiation syndrome during induction therapy, prednisone (0.5 mg/kg body weight daily throughout the induction period) 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 the 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 be performed as 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 may 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 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 leading to hypokalaemia or hypomagnesaemia. In clinical studies conducted in relapsed/refractory patients, at least one instance of corrected QT interval (QTc) prolongation exceeding 500 ms was observed in 40% of patients treated with arsenic trioxide. QTc prolongation was observed between the first and fifth week after arsenic trioxide infusion, with return to baseline within eight weeks of arsenic trioxide infusion. In one patient (who was concomitantly receiving several medicinal products including amphotericin B), asymptomatic torsades de pointes occurred during induction treatment of APL relapse 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 prolongation. In one newly diagnosed patient, induction therapy was discontinued due to severe QTc prolongation and electrolyte abnormalities on day 3 of induction therapy. Recommendations for ECG and electrolyte monitoring Before initiating arsenic trioxide therapy, a 12-lead ECG must be performed and serum electrolyte levels (potassium, calcium and magnesium) and creatinine must be assessed; pre-existing electrolyte abnormalities must be corrected and, if possible, medicinal products that cause QT prolongation should be discontinued. Cardiac function of patients with risk factors for QTc prolongation or risk factors for torsades de pointes should be continuously monitored (by ECG). If the QTc interval is longer than 500 ms, corrective measures must be completed and the QTc interval must be reassessed by serial ECGs; if possible, specialist advice may be sought before considering administration of arsenic trioxide. During treatment with arsenic trioxide, 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 reassessed and immediate steps must be taken to correct concomitant risk factors, if present, while the risks and benefits of continuing or discontinuing arsenic trioxide therapy should be considered. If syncope, rapid or irregular heartbeat occurs, the patient should be hospitalised and continuously monitored, serum electrolytes must be assessed and arsenic trioxide therapy must be temporarily interrupted until the QTc interval decreases to 460 ms, electrolyte abnormalities are corrected and syncope and irregular heartbeat have resolved. After recovery, treatment should be restarted at a dose corresponding to 50% of the previous daily dose. If QTc prolongation does not recur within 7 days of resumption of treatment at the reduced dose, arsenic trioxide therapy may be restarted 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 the group of newly diagnosed low-to-intermediate risk APL patients, 63.2% of them experienced grade 3 or 4 hepatotoxic effects during induction or consolidation therapy with arsenic trioxide in combination with ATRA (see section 4.8 ). However, the toxic effects resolved upon temporary interruption of arsenic trioxide, ATRA or both. Arsenic trioxide treatment must be discontinued before the planned end of treatment whenever grade 3 or higher hepatotoxicity is detected according to the National Cancer Institute Common Toxicity Criteria. Once bilirubin, SGOT and/or alkaline phosphatase concentrations have decreased below four times the upper limit of normal, arsenic trioxide therapy should be restarted at a dose corresponding to 50% of the previous dose for the first 7 days. Thereafter, if prior toxicity does not worsen again, arsenic trioxide therapy may be resumed at full dose. If hepatotoxicity recurs, arsenic trioxide therapy must be permanently discontinued. Dose adjustment Treatment with arsenic trioxide must be temporarily interrupted 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 if this toxicity is considered potentially related to arsenic trioxide treatment (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 As 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 As no data are available for all groups of hepatic impairment and hepatotoxic effects may occur during treatment with arsenic trioxide, 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 the elderly. 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 10 3 /μl). There appeared to be no relationship between baseline white blood cell count and the development of hyperleukocytosis, nor any correlation between baseline white blood cell count and peak white blood cell count. Hyperleukocytosis was never treated with additional chemotherapy and resolved with continued arsenic trioxide treatment. White blood cell counts during consolidation were not as high as during induction treatment and were up to 10 x 10 3 /μl, with the exception of one patient whose white blood cell count during consolidation was 22 x 10 3 /μl. Twenty patients with relapsed/refractory APL (50%) developed leukocytosis, but in all these patients white blood cell counts decreased or normalised by the time bone marrow remission occurred, and cytotoxic chemotherapy or leukapheresis were 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 initiation of treatment, hydroxycarbamide should be administered. Hydroxycarbamide at an appropriate dose should be continued to maintain a white blood cell count ≤ 10 x 10 3 /μl, and then the dose should be gradually reduced. Table 1 Recommendations for initiation of hydroxycarbamide treatment White blood cell count Hydroxycarbamide 10-50 x 10 3 /µl 500 mg four times daily > 50 x 10 3 /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. Wernicke's encephalopathy has been reported following arsenic trioxide treatment in patients with vitamin B1 deficiency. After initiation of arsenic trioxide, patients at risk of vitamin B1 deficiency should be closely monitored for signs and symptoms of encephalopathy. Some cases resolved following 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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