Arsenic Trioxide Phebra (arsenic trioxide 1mg/ml concentrate for solution for infusion): Please refer to full Summary of Product Characteristics (SmPC) before prescribing. Presentation: Each 10ml vial of Arsenic Trioxide Phebra contains 10mg of arsenic trioxide. Indications: Arsenic Trioxide Phebra is indicated for induction of remission and consolidation in adult patients with newly diagnosed low-to-intermediate acute promyelocytic leukaemia (APML) in combination with all-trans-retinoic acid (ATRA) and those with relapsed/refractory APML, characterised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor alpha (PML/RAR-α) gene. Dosage: Newly diagnosed low-to-intermediate risk APML Induction treatment schedule: 0.15 mg/kg/day given daily until complete remission is achieved. If complete remission has not occurred by day 60, dosing must be discontinued. Consolidation schedule: 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 APML Induction treatment schedule: 0.15 mg/kg/day given daily until complete remission is achieved (less than 5% blasts present in cellular bone marrow with no evidence of leukaemic cells). If complete remission has not occurred by day 50, dosing must be discontinued. Consolidation schedule (3 to 4 weeks after completion of induction therapy): 0.15 mg/kg/day for 25 doses given 5 days per week, followed by 2 days interruption, repeated for 5 weeks. Refer to SmPC for full dosage information. Posology: The same dose is recommended for adults and elderly. Paediatric Population: Safety and efficacy not established. Hepatic and Renal Impairment: No data available. Method of administration: Arsenic Trioxide Phebra must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and the special monitoring procedures. Arsenic Trioxide Phebra must be administered intravenously over 1-2 hours. The infusion duration may be extended 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 ensure adequate monitoring. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Special Warning and Precautions: Leukocyte activation syndrome (APML differentiation syndrome): Retinoic-acid-acute promyelocytic leukaemia (RA-APML) or APML differentiation syndrome has been reported. This syndrome can be fatal. 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. ECG and electrolyte monitoring recommendations: Prior to starting arsenic trioxide, 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 should be monitored with continuous cardiac monitoring (ECG). Hepatotoxicity (grade 3 or greater): Hepatotoxicity has been reported in newly diagnosed low-to-intermediate APML patients. Dose delay and modification: Treatment must be temporarily interrupted for any grade 3 or greater toxicity on the National Cancer Institute Common Toxicity Criteria. Laboratory tests: Electrolyte and glycaemia levels, haematologic, hepatic, renal and coagulation parameter tests must be monitored at least twice weekly, and more frequently for clinically unstable patients.

Patients with renal or hepatic impairment: Caution is advised as no data available. Elderly: Caution is advised as data is limited. Hyperleukocytosis: Hyperleukocytosis has been reported in some newly diagnosed and relapsed/refractory APML patients. Development of second primary malignancies: Arsenic trioxide is a human carcinogen; patients should be monitored for second primary malignancies. Encephalopathy: Cases of encephalopathy have been reported. Patients at risk of B1 deficiency should be closely monitored. Sodium content: Arsenic Trioxide Phebra contains less than 1 mmol sodium (23mg) per 10mL. Interactions: Caution should be observed when arsenic trioxide is combined with medical products that prolong QT/QTc interval, cause hepatotoxic effects, and other antileukaemic agents. Fertility, Pregnancy and Lactation: Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies. No available data in pregnant women. Breast-feeding is contra-indicated during treatment with arsenic trioxide. No fertility studies have been performed. Effects on ability to drive and use machines: Negligible influence. Undesirable Effects: Adverse reactions in patients receiving arsenic trioxide: very common (≥ 1/10) hyperglycaemia, hypokalaemia, hypomagnesaemia, paraesthesia, dizziness, headache, tachycardia, differentiation syndrome, dyspnoea, diarrhoea, vomiting, myalgia, nausea, pruritus, rash, pyrexia, pain, fatigue, oedema, alanine amino transferase increased, aspartate amino transferase increased, electrocardiogram QT prolonged; common (≥ 1/100 to < 1/10) herpes zoster, febrile neutropenia, leucocytosis, neutropenia, pancytopenia, thrombocytopenia, anaemia, hypernatraemia, ketoacidosis, hypermagnesaemia, convulsion, vision blurred, pericardial effusion, ventricular extrasystoles, vasculitis, hypotension, hypoxia, pleural effusion, pleuritic pain, pulmonary alveolar haemorrhage, abdominal pain, erythema, face oedema, arthralgia, bone pain, renal failure, chest pain, chills, hyperbilirubinaemia, blood creatinine increased, weight increased. Please consult the Summary of Product Characteristics for a full description of adverse reactions. Overdose: If acute arsenic toxicity symptoms appear, arsenic trioxide must be immediately discontinued and chelating therapy with penicillamine considered. Refer to SmPC for full details. Pharmaceutical Precautions: Do not mix or administer as an infusion with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Do not freeze. Dilute with 100 to 250 ml of glucose 50 mg/ml (5%) solution for injection or sodium chloride 9 mg/ml (0.9%) solution for injection. Diluted solutions may be stored at 15°C – 30°C for up to 48 hours or at 2°C – 8°C for up to 72 hours. Inspect visually before administration; do not administer if any discoloration or particulate matter is observed. Legal Category: POM. Packs size and NHS price: 10 x 10ml vials £2700.00. Marketing Authorisation number: PL 42973/0007 Marketing Authorisation Holder: Phebra Limited, 24-25 New Bond Street, 1st Floor, London, England, W1S 2RR. Distributed in the UK by Flexipharm Austrading Limited, Farnborough, GU14 7XA. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Further information on request: Flexipharm Austrading Limited via inquiries@flexipharmaustrading.com or 01628 290433. For medical information please contact 01480 273425 or medinfo@cambreg.co.uk Date of preparation/last revised: May 2020. References: Arsenic Trioxide Phebra 1 mg/ml concentrate for solution for infusion Summary of Product Characteristics.