Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

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

Leukocyte activation syndrome (APL differentiation syndrome)

27% of patients with APL, in the relapsed/refractory setting, treated with arsenic trioxide have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukaemia (RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis. This syndrome can be fatal.

In newly diagnosed APL patients treated with arsenic trioxide and all-trans-retinoic acid (ATRA), APL differentiation syndrome was observed in 19 % including 5 severe cases. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), treatment with ARSENIC TRIOXIDE S.K. 1MG/ML must be temporarily discontinued and high-dose steroids (dexamethasone 10 mg intravenously twice a day) must be immediately initiated, irrespective of the leukocyte count and continued for at least 3 days or longer until signs and symptoms have abated. If clinically justified/required, concomitant diuretic therapy is also recommended. The majority of patients do not require permanent termination of ARSENIC TRIOXIDE S.K. 1MG/ML therapy during treatment of the APL differentiation syndrome. As soon as signs and symptoms have subsided, treatment with ARSENIC TRIOXIDE S.K. 1MG/ML can be resumed at 50 % of the previous dose during the first 7 days.
Thereafter, in the absence of worsening of the previous toxicity, ARSENIC TRIOXIDE S.K. 1MG/ML might be resumed at full dosage. In the case of the reappearance of symptoms ARSENIC TRIOXIDE S.K. 1MG/ML should be reduced to the previous dosage. In order to prevent the development of the APL differentiation syndrome during induction treatment, prednisone (0.5 mg/kg body weight per day throughout induction treatment) may be administered from day 1 of ARSENIC TRIOXIDE S.K. 1MG/ML application to the end of induction therapy in APL patients. It is recommended that chemotherapy not be added to treatment with steroids since there is no experience with administration of both steroids and chemotherapy during treatment of the leukocyte activation syndrome due to ARSENIC TRIOXIDE S.K. 1MG/ML. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancy. Monitoring and management for these patients should be as described above.
Electrocardiogram (ECG) abnormalities

Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. Previous treatment with anthracyclines may increase the risk of QT prolongation. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products (such as class Ia and III antiarrythmics (e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazine), antidepressants (e.g. amitriptyline), some macrolides (e.g. erythromycin), some antihistamines (e.g.
terfenadine and astemizole), some quinolone antibiotics (e.g. sparfloxacin), and other individual medicinal products known to increase QT interval (e.g. cisapride)), a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, amphotericin B or other conditions that result in hypokalaemia or hypomagnesaemia. In clinical trials, in the relapsed/refractory setting, 40 % of patients treated with ARSENIC TRIOXIDE experienced at least one QT corrected (QTc) interval prolongation greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after ARSENIC TRIOXIDE infusion, and then returned to baseline by the end of 8 weeks after ARSENIC TRIOXIDE infusion. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide. In newly diagnosed APL patients 15.6 % showed QTc prolongation with arsenic trioxide in combination with ATRA (see section 4.8). In one newly diagnosed patient induction treatment was terminated because of severe prolongation of the QTc interval and electrolyte abnormalities on day 3 of induction treatment.

ECG and electrolyte monitoring recommendations

Prior to initiating therapy with ARSENIC TRIOXIDE S.K. 1MG/ML, a 12-lead ECG must be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; pre-existing electrolyte abnormalities must be corrected and, if possible, medicinal products that are known to prolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or risk factors of torsade de pointes should be monitored with continuous cardiac monitoring (ECG). For QTc greater than 500 msec, corrective measures must be completed and the QTc reassessed with serial ECGs and, if available, a specialist advice could be sought prior to considering using ARSENIC TRIOXIDE S.K. 1MG/ML. During therapy with ARSENIC TRIOXIDE S.K. 1MG/ML, potassium concentrations must be kept above 4 mEq/l and magnesium concentrations must be kept above 1.8 mg/dl. Patients who reach an absolute QT interval value > 500 msec must be reassessed and immediate action must be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending ARSENIC TRIOXIDE S.K. 1MG/ML therapy must be considered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and monitored continuously, serum electrolytes must be assessed, ARSENIC TRIOXIDE S.K. 1MG/ML therapy must be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. After recovery, treatment should be resumed at 50 % of the preceding daily dose. If QTc prolongation does not recur within 7 days of restarting treatment at the reduced dose, treatment with ARSENIC TRIOXIDE S.K. 1MG/ML can be resumed at 0.11 mg/kg body weight per day for a second week. The daily dose can be escalated back to 100 % of the original dose if no prolongation occurs.
There are no data on the effect of arsenic trioxide on the QTc interval during the infusion. Electrocardiograms must be obtained twice weekly, and more frequently for clinically unstable patients, during induction and consolidation.
Hepatotoxicity (grade 3 or greater)

In newly diagnosed patients with low to intermediate risk APL 63.2 % developed grade 3 or 4 hepatic toxic effects during induction or consolidation treatment with arsenic trioxide in combination with ATRA (see section 4.8). However, toxic effects resolved with temporary discontinuation of either arsenic trioxide, ATRA or both. Treatment with ARSENIC TRIOXIDE S.K. 1MG/ML must be discontinued before the scheduled end of therapy at any time that a hepatotoxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed. As soon as bilirubin and/or SGOT and/or alkaline phosphatase are decreased to below 4 times the normal upper level, treatment with ARSENIC TRIOXIDE S.K. 1MG/ML should be resumed at 50 % of the previous dose during the first 7 days. Thereafter, in absence of worsening of the previous toxicity, ARSENIC TRIOXIDE S.K. 1MG/ML should be resumed at full dosage. In case of reappearance of hepatotoxicity, ARSENIC TRIOXIDE S.K. 1MG/ML must be permanently discontinued.

Dose delay and modification

Treatment with ARSENIC TRIOXIDE S.K. 1MG/ML must be temporarily interrupted before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed and judged to be possibly related to ARSENIC TRIOXIDE S.K. 1MG/ML treatment. (see section 4.2)

Laboratory tests

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

Renal impairment

Since no data are available across all renal impairment groups, caution is advised in the use of ARSENIC TRIOXIDE S.K. 1MG/ML in patients with renal impairment. The experience in patients with severe renal impairment is insufficient to determine if dose adjustment is required.

The use of ARSENIC TRIOXIDE in patients on dialysis has not been studied.

Hepatic impairment
Since no data are available across all hepatic impairment groups and hepatotoxic effects may occur during the treatment with arsenic trioxide caution is advised in the use of ARSENIC TRIOXIDE S.K. 1MG/ML in patients with hepatic impairment (see section 4.4 on hepatotoxicity and section 4.8). The experience in patients with severe hepatic impairment is insufficient to determine if dose adjustment is required.

Elderly

There is limited clinical data on the use of ARSENIC TRIOXIDE in the elderly population. Caution is needed in these patients.

Hyperleucocytosis

Treatment with arsenic trioxide has been associated with the development of hyperleukocytosis (≥ 10 x 103/ μl) in some relapsed/refractory APL patients. There did not appear to be a relationship between baseline white blood cell (WBC) counts and development of hyperleucocytosis nor did there appear to be a correlation between baseline WBC count and peak WBC counts. Hyperleucocytosis was never treated with additional chemotherapy and resolved on continuation of ARSENIC TRIOXIDE. WBC counts during consolidation were not as high as during induction treatment and were < 10 x 103/μl, except in one patient who had a WBC count of 22 x 103/μl during consolidation. Twenty relapsed/refractory APL patients (50 %) experienced leucocytosis;
however, in all these patients, the WBC count was declining or had normalized by the time of bone marrow remission and cytotoxic chemotherapy or leucopheresis was not required. In newly diagnosed patients with low to intermediate risk APL leucocytosis developed during induction therapy in 35 of 74 (47 %) patients (see section 4.8). However all cases were successfully managed with hydroxyurea therapy.

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

Table 1 Recommendation for initiation of hydroxyurea

WBC                                Hydroxyurea
10–50 x 103/μl                     500 mg four times a day
> 50 x 103/μl                      1000 mg four times a day

Development of second primary malignancies

The active ingredient of ARSENIC TRIOXIDE S.K. 1MG/ML, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Encephalopathy

Cases of encephalopathy were reported with treatment with arsenic trioxide. Wernicke encephalopathy after arsenic trioxide treatment was reported in patients with vitamin B1 deficiency. Patients at risk of B1 deficiency should be closely monitored for signs and symptoms of encephalopathy after arsenic trioxide initiation. Some cases recovered with vitamin B1 supplementation.

Excipient with known effect

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

Effects on Driving

4.7 Effects on ability to drive and use machines

ARSENIC TRIOXIDE S.K. 1MG/ML has no or negligible influence on the ability to drive and use machines.