Arsenic trioxide parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Concentrate for solution for infusion containing arsenic trioxide.
Drugs List
Therapeutic Indications
Uses
Leukaemia - acute promyelocytic
Induction of remission and consolidation in adult patients with newly diagnosed low to intermediate risk acute promyelocytic leukaemia (APL) in combination with all-trans-retinoic acid (ATRA) and in adult patients with relapsed/refractory 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 Pro-myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha gene).
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols should be consulted.
Adults
Newly diagnosed low to intermediate risk acute promyelocytic leukaemia (APL)
Induction treatment schedule
Arsenic trioxide must be administered intravenously at a fixed dose of 0.15mg/kg/day, given daily until the complete remission is achieved. If complete remission has not occurred by day 60, dosing must be discontinued.
Consolidation schedule
Arsenic trioxide must be administered intravenously at a dose of 0.15mg/kg/day, given for 5 days per week. Treatment should be continued for 4 weeks on and 4 weeks off, for a total of 4 cycles.
Relapsed/refractory APL
Induction treatment schedule
Arsenic trioxide must be administered intravenously at a fixed rate of 0.15mg/kg/day given daily until complete remission is achieved. If complete remission has not occurred by day 50, dosing must be discontinued.
Consolidation schedule
Must begin 3 to 4 weeks after completion of induction therapy.
Arsenic trioxide is to be given intravenously at a dose of 0.15mg/kg/day for 25 doses given 5 days per week, followed by 2 days interruption, repeated for 5 weeks.
Patients with Renal Impairment
The Renal Drug Handbook recommends caution and dose reduction in patients whose the glomerular filtration rate is less than 50ml/minute.
Additional Dosage Information
Discontinue if syncope, rapid or irregular heartbeat develops. Do not reinitiate until QTc interval regresses to below 460 milliseconds and electrolyte disorders are corrected, and the syncope and irregular heartbeat cease.
Post recovery, treatment can be then 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 can be resumed at 0.11mg/kg/day for a second week. The daily dose can be re-escalated to 100% of the original dose if no prolongation occurs.
Discontinue at the first signs of APL differentiation syndrome. High dose steroids must be initiated (10mg dexamethasone intravenously twice a day), irrespective of the leucocyte count, and continued for at least 3 days or longer until signs and symptoms have stopped. Post recovery, resume at 50% of previous dosage for 7 days. Full dosage can then be resumed if no signs of toxicity re-occur. Most patients do not require treatment termination.
Grade 3 (or greater) toxicities: Suspend therapy and only resume treatment after resolution or recovery to baseline. On re-initiation treatment must resume at 50% of the preceding daily dose. The dose can be increased to 100% of the original dose, if no recurrence of toxicity within 7 days of reinitiating. If a recurrence of toxicity occurs, patient must stop treatment.
Hepatotoxicity grade 3 (or greater): Discontinue therapy and resume at 50% of previous dose as soon as bilirubin and/or SGOT and/or alkaline phosphatase are decreased to below 4 times the normal upper level. Full dosage can be resumed after 7 days if no signs of previous toxicity occur.
Administration
For intravenous infusion over 1 to 2 hours. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed.
Contraindications
Children under 5 years
Breastfeeding
Long QT syndrome
Pregnancy
Torsade de pointes
Precautions and Warnings
Children aged 6 to 18 years
Elderly
Family history of long QT syndrome
Females of childbearing potential
History of treatment with anthracyclines
Congestive cardiac failure
Electrolyte imbalance
Hepatic impairment
History of torsade de pointes
Renal impairment
Thiamine deficiency
Correct electrolyte disorders before treatment
Monitor patients at risk of thiamine deficiency for signs of encephalopathy
Treatment should be initiated in hospital
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor haematological parameters before and during treatment
Monitor hepatic function before treatment and regularly during treatment
Monitor renal function before treatment and regularly during treatment
Perform ECG before and during treatment
Consider interrupting treatment if QTc > 500msec
If syncope, rapid or irregular heartbeat develops hospitalise & monitor
Maintain serum magnesium above 1.8mg/dl
Maintain serum potassium above 4mEq/l
Monitor blood glucose
Monitor coagulation values
Monitor patients for development of second primary malignancies
Monitor serum electrolytes
Risk of developing hyperleukocytosis
Predisposition QT prolongation: Counsel patient on symptoms of arrhythmias
Risk of developing acute promyelocytic leukaemia differentiation syndrome
Discontinue if grade 3 or greater adverse reaction that recurs/persists
Interrupt treatment and/or reduce dose for any grade 3 toxicity
Newly diagnosed APL: Discontinue if remission not achieved by day 60
Relapsed/refractory APL: Discontinue if remission not achieved by day 50
Not licensed for use in children under 18 years
Female: Contraception required during and for 6 months after treatment
Male & female: Ensure adequate contraception during treatment
Male: Contraception required during and for 3 months after treatment
In clinical trials, 40% of the patients in the relapsed/refractory setting experienced at least one QTc prolongation greater than 500msec. This was observed between weeks 1 and 5 after treatment started and then returned to baseline by end of week 8.
In 27% of patients with relapsed/refractory APL and in 19% of newly diagnosed APL patients, APL differentiation syndrome was observed. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities), treatment must be stopped temporarily and high-dose steroids should be initiated. There is no experience with the administration of chemotherapy with steroids during treatment of APL differentiation, therefore it is recommended that chemotherapy should not be added to treatment with steroids.
If hyperleukocytosis occurs, it can be resolved on continuation with treatment without additional chemotherapy treatment. In patients who develop hyperleukocytosis after initiation therapy, hydroxycarbamide should be administered and maintained at the appropriate dose in order to keep WBC at or below than 10 x 10 to the power of 3/microlitre and subsequently tapered.
Patients with WBC of 10 to 50 x 10 to the power of 3/microlitre should be given hydroxycarbamide 500mg four times a day. Patients with WBC higher than 50 x 10 to the power of 3/microlitre should be given hydroxycarbamide 1g four times a day.
There does not appear to be a relationship between baseline white blood cell (WBC) count and development of hyperleukocytosis, nor does there appear to be a correlation between baseline WBC count and peak WBC count.
Haematological, hepatic, renal and coagulation parameter tests and glycaemia and electrolytes levels must be monitored at least twice weekly (more frequently for clinically unstable patients) during the induction phase. During the consolidation phase they should be monitored at least once a week.
Pregnancy and Lactation
Pregnancy
Arsenic trioxide is contraindicated during pregnancy.
Manufacturer advises if arsenic trioxide is used during pregnancy, or the patient becomes pregnant during therapy, the patient must be warned of the potential risk to the foetus.
At the time of writing there have been no studies in pregnant women.
Animal studies have shown arsenic trioxide to be embryotoxic and teratogenic.
Lactation
Arsenic trioxide is contraindicated during breastfeeding.
Manufacturer advises due to the potential for serious adverse reactions in nursing infants, breastfeeding must be discontinued prior to and during treatment with arsenic trioxide.
Arsenic is excreted in human breast milk.
Side Effects
Abdominal pain
Acute promyelocytic leukaemia differentiation syndrome
Alveolar haemorrhages
Anaemia
Arthralgia
Atrial fibrillation
Atrial flutter
Atrioventricular block
Blurred vision
Bone pain
Cardiac failure
Chest pain
Chills
Confusion
Convulsions
Dehydration
Diarrhoea
Dizziness
Dyspnoea
ECG changes
Encephalopathy
Erythema
Facial oedema
Fatigue
Febrile neutropenia
Fluid retention
Gamma glutamyl transferase (GGT) increased
Haemorrhage
Headache
Herpes zoster
Hyperbilirubinaemia
Hyperglycaemia
Hypermagnesaemia
Hypernatraemia
Hypokalaemia
Hypomagnesaemia
Hypotension
Hypoxia
Increase in ALT level
Increase in AST level
Increase in creatinine
Infections
Intravascular coagulation (disseminated)
Ketoacidosis
Leucocytosis
Leucopenia
Lymphopenia
Myalgia
Nausea
Neutropenia
Oedema
Pain
Pancytopenia
Paraesthesia
Pericardial effusion
Peripheral neuropathy
Pleural effusion
Pleuritic pain
Pneumonia
Pneumonitis
Prolongation of QT interval
Pruritus
Pulmonary infiltrates
Pyrexia
Rash
Renal failure
Sepsis
Tachycardia
Thrombocytopenia
Torsades de pointes
Vasculitis
Ventricular extrasystoles
Ventricular tachycardia
Vomiting
Weight gain
Wernicke encephalopathy
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: June 2020
Reference Sources
Summary of Product Characteristics: Trisenox 1mg/ml concentrate for solution for infusion. Teva Pharma B.V. Revised November 2019.
Summary of Product Characteristics: Trisenox 2mg/ml concentration for solution for infusion. Teva Pharma B.V. Revised May 2022.
Summary of Product Characteristics: Arsenic Trioxide Phebra 1mg/1ml concentrate for solution for infusion. Flexipharm Austrading Limited. Revised May 2021.
Summary of Product Characteristics: Arsenic Trioxide STADA 1mg/1ml concentrate for solution for infusion. Thornton & Ross Ltd. Revised July 2019.
The Renal Drug Handbook. Fifth Edition (2019) ed. Ashley, C. and Dunleavy, A. Radcliffe Publishing Ltd, London.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 20 October 2021
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