Trisenox

HOS-093228 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile Related adverse reactions of CTC grade 3 and 4 occurred in 37 % of relapsed/refractory APL patients in clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leucocytosis occurred in 50 % of patients with relapsed/refractory APL, as determined by haematology assessments. Serious adverse reactions were common (1-10 %) and not unexpected in the relapsed/refractory population. Those serious adverse reactions attributed to arsenic trioxide included APL differentiation syndrome (3), leucocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrial fibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related to haemorrhage, infections, pain, diarrhoea, nausea. 7 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 tended to tolerate consolidation and maintenance treatment with less toxicity than in induction. This is probably due to the confounding of adverse events by the uncontrolled disease process early on in the treatment course and the myriad concomitant medicinal products required to control symptoms and morbidity. In a phase 3, multicentre, non-inferiority trial comparing all-trans-retinoic acid (ATRA) plus chemotherapy with ATRA plus arsenic trioxide in newly diagnosed low-to-intermediate risk APL patients (Study APL0406; see also section 5.1), serious adverse reactions including hepatic toxicity, thrombocytopenia, neutropenia and QTc prolongation were observed in patients treated with arsenic trioxide. Tabulated list of adverse reactions The following undesirable effects have been reported in clinical trials and/or post-marketing experience in newly diagnosed and relapsed/refractory APL patients. Undesirable effects are listed in table 2 below as MedDRA preferred term by system organ class and frequencies 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

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HOS-093224 · has-contraindication-information · PDF-Seite 4

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

HOS-093223 · has-indication-information · PDF-Seite 2

TRISENOX 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) (previous treatment should have included a retinoid and chemotherapy) characterised by the presence of the t(15;17) translocation and/or the presence of the promyelocytic leukaemia/retinoic-acid-receptor-alpha (PML/RAR-alpha) gene. The response rate of other acute myelogenous leukaemia subtypes to arsenic trioxide has not been examined.

HOS-093226 · has-interaction-information · PDF-Seite 6

No formal assessments of pharmacokinetic interactions between TRISENOX and other therapeutic medicinal products have been conducted. Medicinal products known to cause QT/QTc interval prolongation, hypokalaemia or hypomagnesaemia QT/QTc prolongation is expected during treatment with arsenic trioxide, and torsade de pointes and complete heart block have been reported. Patients who are receiving, or who have received, medicinal products known to cause hypokalaemia or hypomagnesaemia, such as diuretics or amphotericin B, 6 may be at higher risk for torsade de pointes. Caution is advised when TRISENOX is co-administered with other medicinal products known to cause QT/QTc interval prolongation such as macrolide antibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalaemia or hypomagnesaemia. Additional information about QT prolonging medicinal agents, is provided in section 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 (see section 4.4 and 4.8). Other antileukaemic medicinal products The influence of TRISENOX on the efficacy of other antileukaemic medicinal products is unknown.

HOS-093227 · has-pregnancy-information · PDF-Seite 7

Contraception in males and females Due to the genotoxic risk of arsenic compounds (see section 5.3), women of childbearing potential must use effective contraceptive measures during treatment with TRISENOX and for 6 months following 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. Pregnancy 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 this product, the patient must be informed of the potential harm to the foetus. Breast-feeding Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding infants and children from TRISENOX, breast-feeding must be discontinued prior to and throughout administration and for two weeks after the last dose. Fertility No clinical or non-clinical fertility studies have been conducted with TRISENOX.

HOS-093225 · has-warning-information · PDF-Seite 4

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 TRISENOX 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 TRISENOX therapy during treatment of the APL differentiation syndrome. As soon as signs and symptoms have subsided, treatment with TRISENOX can be resumed at 50 % of the previous dose during the first 7 days. Thereafter, in the absence of worsening of the previous toxicity, TRISENOX might be resumed at full dosage. In the case of the reappearance of symptoms TRISENOX 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 TRISENOX 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 TRISENOX. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancy. Monitoring a

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