Arsenic Trioxide

Registered South African indications:

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.

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The response rate of other acute myelogenous leukaemia subtypes to arsenic trioxide has not been examined

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Heart block or prolonged QT intervals
• Congestive cardiac failure
• Co-administration with medicines that prolong the QT interval
• Pregnancy
• Breastfeeding

South African recommendations

Caution in the following patient groups

• Renal impairment
• Hepatic impairment
• Elderly
• Women of childbearing potential
• Men of childbearing potential

Administration/monitoring

• Arsenic trioxide must be administered under the supervision of a medical practitioner experienced in managing acute leukaemia
• Clinically unstable acute promyelocytic leukaemia (APL) patients are at higher risk and require more frequent monitoring of haematologic, hepatic, renal, and coagulation parameters, as well as electrolyte and glycaemia levels

APL Differentiation Syndrome

• Patients with APL treated with arsenic trioxide may experience APL differentiation syndrome, which is characterised by fever, dyspnoea, weight gain, pulmonary infiltrates, and effusions (pleural or pericardial). This syndrome can be fatal
• Treatment involves promptly administering high-dose steroids (e.g. dexamethasone 10mg IV every 12 hours) and temporarily reducing or stopping the dose of arsenic trioxide and/or tretinoin (ATRA) until symptoms resolve

Electrocardiogram (ECG) abnormalities

• Treatment with arsenic trioxide is expected to cause QT interval prolongation (which can lead to the fatal ventricular arrhythmia torsades de pointes) and has been associated with complete atrioventricular (AV) block
• The risk of the fatal arrhythmia is increased by the extent of QT prolongation, history of torsades de pointes, pre-existing QT interval prolongation, congestive heart failure, and concurrent use of potassium-depleting diuretics or other QT prolonging medicines, or conditions resulting in hypokalaemia or hypomagnesaemia

ECG and electrolyte monitoring recommendations (see Monitoring)

• Do not administer arsenic trioxide to patients with congestive heart failure
• Prior to starting therapy, a 12-lead ECG and assessment of serum electrolytes (potassium, calcium, and magnesium) and creatinine are required; pre-existing electrolyte abnormalities must be corrected, and QT-prolonging medicines should be discontinued. Therapy should be withheld if the QTc is over 500msec until corrective measures are complete and the QTc is reassessed
• During therapy, maintain potassium levels above 4mmol/L and magnesium levels above 0.8mmol/L
• Discontinue arsenic trioxide if the absolute QTc interval exceeds 500msec, or if the patient develops syncope or a rapid/irregular heart beat. Therapy can be cautiously resumed at a reduced dose when the QTc is below 460msec and symptoms/abnormalities have resolved
• ECGs must be obtained twice weekly, and more frequently for clinically unstable patients, during induction and consolidation phases

Peripheral neuropathy

• Peripheral neuropathy has been associated with arsenic trioxide use; patients on continuing treatment may be at greater risk
• Patients should be monitored periodically for symptoms or signs of neuropathy, as severe cases may require discontinuation of arsenic trioxide

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 and tretinoin (ATRA)
• Treatment with arsenic trioxide must be discontinued at any time that a hepatotoxicity grade 3 or greater (on the NCI-CTC scale) is observed
• Therapy may be cautiously resumed at 50% of the previous dose once bilirubin, SGOT, and/or alkaline phosphatase levels decrease to below 4 times the normal upper limit
• Permanent discontinuation of arsenic trioxide is required if hepatotoxicity reappears

Hyperleukocytosis

• Treatment with arsenic trioxide, particularly in combination with tretinoin (ATRA), is associated with the development of hyperleukocytosis ≥10 x 10⁹/L
• This may be managed with hydroxyurea (e.g. 500mg or 1.0g four times daily) until the White Blood Cell (WBC) count decreases to <10 x 10⁹/L
• In some protocols, prophylactic steroids (e.g. prednisone/prednisolone 1mg/kg/day were used until the WBC count fell below the threshold as a safeguard against hyperleukocytosis

Paediatric use

• There are limited clinical data on the paediatric use of arsenic trioxide

Dose delay and modification

• Treatment must be temporarily interrupted before the scheduled end of therapy at any time a toxicity grade 3 or greater (on the NCI-CTC scale) is observed and judged to be possibly related to arsenic trioxide

Laboratory and ECG monitoring (see Monitoring)

• Electrolyte and glycaemia levels, along with haematologic, hepatic, renal, and coagulation parameter tests, must be monitored at least twice weekly during induction and at least weekly during consolidation (more frequently for clinically unstable patients)
• ECGs should be obtained weekly (and more frequently for clinically unstable patients) during induction and consolidation

Development of second primary malignancies

• The active ingredient, arsenic trioxide, is a human carcinogen
• Patients must be monitored for the development of second primary malignancies

Encephalopathy

• Cases of encephalopathy, including Wernicke encephalopathy, have been reported with arsenic trioxide treatment, particularly in patients with vitamin B₁ deficiency
• Patients at risk of B₁ deficiency should be closely monitored for signs and symptoms of encephalopathy after starting arsenic trioxide, as some cases recovered with B₁ supplementation

Sodium content

• Arsenic trioxide contains less than 1mmol sodium (23mg) per 10ml, that is to say essentially ‘sodium-free’

Effects on ability to drive and use machines

• Arsenic trioxide can cause seizures and headache and may have an influence on mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Arsenic trioxide must be administered under the supervision of a medical practitioner who is experienced in the management of acute leukaemias, and the special monitoring procedures must be followed

Cycles of treatment are given to achieve complete remission (CR), defined as the complete disappearance of all leukaemic myeloblasts and promyelocytes and <5% overall myeloblasts by morphological examination of the marrow. After induction of remission, consolidation cycles may be given, and maintenance therapy considered. arsenic trioxide may be given in combination with all-trans retinoic acid (ATRA) and/or chemotherapy.

In patients with newly diagnosed/ de novo APL combination treatment
- Arsenic trioxide may be given in combination with all-trans-retinoic acid (ATRA) and/or chemotherapy

• Dosage regimens for low to intermediate risk patients are described in the table below:

Category of patients	Treated with:	Induction (Cycle 1)	Consolidation (4 cycles)
WBC count ≤10 x 109/L	Arsenic trioxide	0.15mg/kg/day from day 1 until haematological CR or for a maximum of 60 days. If no haematological CR is achieved by day 60 discontinue treatment	0.15mg/kg/day, 5 days per week. 4 weeks on and 4 weeks off, for a total of 4 cycles
	ATRA (Tretinoin)	Dose as per the prescribing information of ATRA

Chemotherapy with idarubicin (IV) on Days 2, 4, 6 and 8. The idarubicin dose is age-dependent and given at the induction phase only based on a patients’ ability to tolerate

During induction

• It is strongly recommended that during induction, patients be treated with prednisone (or prednisolone): 1mg/kg/day for ≥10 days; Aggressive platelet and plasma support should also be considered to maintain haemostatic targets

Patients in CR

• For patients in CR after the 3 cycles of induction/consolidation: Maintenance: ATRA from Day 1–14; Followed by: 6-mercaptopurine (6MP) and methotrexate (MTX) both from Day 15-90 (each cycle 3 months); Then be admin. for 24 months

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In the Lo-Coco trial, marrow samples were collected at the end of the third consolidation cycle and tested by RT-PCR for assessment of molecular remission. Patients who did not achieve molecular remission at the end of the entire consolidation programme were considered as molecular resistant and taken off the treatment

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In patients refractory to, or relapsed from retinoid and anthracycline therapy

Induction treatment therapy

• IV: For induction: Daily infusion: 0.15mg/kg/day, continue until bone marrow remission is obtained; If bone marrow remission is not obtained by day 60: Dosing must be discontinued

Consolidation treatment therapy

An additional course beginning consolidation of treatment must begin 3-4 weeks after completion of the induction cycle:

• IV: 0.15mg/kg/day, for 25 doses given 5 days per week; Followed by 2 days of interruption, repeated for 5 weeks

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Dose modification and re-initiation in refractory to, or relapsed from retinoid and anthracycline therapy

Treatment with arsenic trioxide must be interrupted, adjusted, or discontinued before the scheduled end of therapy at any time that a toxicity grade 3 or greater, based on the National Cancer Institute Common Toxicity Criteria, is observed and judged to be possibly related to arsenic trioxide treatment
Patients who experience such reactions that are considered arsenic trioxide-related must resume treatment only after resolution of the toxic event or after recovery to baseline status of the abnormality that prompted the interruption. In such cases, treatment must resume at 50% of the preceding daily dose. If the toxic event does not recur within 3 days of restarting treatment at the reduced dose, the daily dose can be escalated back to 100% of the original dose. Patients who experience a recurrence of toxicity must be removed from treatment
For ECG, electrolytes abnormalities and hepatotoxicity, see Monitoring

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Method of administration
Arsenic trioxide 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

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For instructions on preparation of the medicinal product before administration, and for special precautions for disposal and other handling, see Additional Prescriber Points

Not established for use in children up to 17 years

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The safety and efficacy of arsenic trioxide in children aged up to 17 years has not been established. No data are available for children under 5 years

Pregnancy

South African recommendations

• Contraindicated
• Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies. There are no studies in pregnant women using arsenic trioxide
• Arsenic trioxide should not be given to patients who are pregnant
• If a patient becomes pregnant while taking this product, the patient must be informed of the potential harm to the foetus
• Pregnancy test prior to the treatment with arsenic trioxide should be performed

Contraception in males and females

• Due to the genotoxic risk of arsenic compounds, women of childbearing potential and men must use effective contraceptive measures while they are being treated with arsenic trioxide and for 6 months following completion of treatment
• Men should use effective contraceptive measures and be advised not to father a child while receiving arsenic trioxide and for 3 months following completion of treatment

Breastfeeding

South African recommendations

• Contraindicated
• Arsenic is excreted in human milk
• Because of the potential for serious adverse reactions in nursing infants and children from arsenic trioxide, breastfeeding must be discontinued prior to and throughout administration and for two weeks after the last dose

Fertility

South African recommendations

• No clinical or non-clinical fertility studies have been conducted with arsenic trioxide

South African recommendations

• Caution; no dose adjustment recommended
  Since no data are available across all renal impairment groups, caution is advised in the use of arsenic trioxide in patients with renal impairment
  In a pharmacokinetic study of arsenic trioxide, the plasma clearance of AsIII was not altered in patients with mild renal impairment (CrCl of 50-80ml/min) or moderate renal impairment (CrCl of 30-49ml/min)
  The plasma clearance of AsIII in patients with severe renal impairment (CrCl<30ml/min) was 40% lower when compared with patients with normal renal function

• Experience in patients with severe renal impairment is insufficient to determine if a dose adjustment is required; the use in patients on dialysis has not been studied

South African recommendations

• Caution; no dose adjustment recommended
  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 in patients with hepatic impairment
  Recommendations for dose reduction of arsenic trioxide for hepatotoxicity:
  No formal studies have been conducted in patients with severe hepatic impairment. In the APML 4 study, the dose of arsenic trioxide was decreased to 0.08mg/kg/day for grade 3 hepatotoxicity and temporarily discontinued for grade 4 hepatotoxicity
  After temporary discontinuation arsenic trioxide was restarted at 0.08mg/kg/day when the liver function test (LFT) improved to grade 2 or better. Consider increasing back to 0.15mg/kg/day if no deterioration after 1 week
  There is insufficient experience in patients with severe hepatic impairment to determine if a dose adjustment is required

South African recommendations

• Caution; no dose adjustment recommended
  Clinical data in the elderly are limited
  Particular caution is needed in the elderly because they have a greater risk of reduced renal function, and renal excretion is the main route of arsenic elimination

Infections and Infestations

Very common

• Infection

Blood and the Lymphatic System Disorders

Very common

• Leukocytosis
• Neutropenia
• Thrombocytopenia

Common

• Febrile neutropenia (all grades and Grade >3 frequencies)
• Haemorrhage
• Thrombosis

Uncommon

• Leucopenia
• Vasculitis

Immune System Disorders

Rare

• Immune suppression causing herpes zoster

Metabolism and Nutrition Disorders

Very common

• Hepatotoxicity

Common

• Hypokalaemia
• Hyperglycaemia
• Increase in aspartate aminotransferase (AST)
• Increase in alanine transaminase (ALT)
• Increase in gamma-glutamyl transferase (GGT)
• Increase in bilirubin
• Liver dysfunction

Uncommon

• Hypermagnesaemia
• Hypernatraemia
• Ketoacidosis

Nervous System Disorders

Common

• Headache
• Insomnia
• Peripheral neuropathy
• Paraesthesia
• Mood alteration
• Musculoskeletal pain
• Seizures

Cardiac Disorders

Very common

• Dysrhythmia including non-sustained ventricular tachycardia
• Premature ventricular contractions
• QTc-prolongation

Common

• Torsade de pointes¹
• Ventricular tachycardia

Uncommon

• CVA (cerebral vascular accident)
• Pericardial effusion

Respiratory, Thoracic and Mediastinal Disorders

Common

• Cough
• Sore throat
• Dyspnoea
• Pleuritic pain

Uncommon

• Pulmonary alveolar haemorrhage
• Pleural effusion
• Hypoxia

Gastrointestinal Disorders

Common

• Nausea
• Vomiting
• Diarrhoea
• Abdominal pain
• Mucositis

Skin and Subcutaneous Tissue Disorders

Common

• Rash
• Pruritus

Uncommon

• Dermatitis
• Erythema

Musculoskeletal, Connective Tissue and Bone Disorders

Common

• Bone pain
• Arthralgia
• Musculoskeletal pain

Renal and Urinary Disorders

Uncommon

• Renal failure

General Disorders and Administrative Site Conditions

Very common

• Fever²

Common

• Fatigue
• APL differentiation syndrome

Uncommon

• Chest pain
• Pain

Investigations

Very common

• Increased alanine amino transferase (all Grades)
• Increase in aspartate amino transferase (all Grades)

Common

• ECG QT prolongation
• Increase in alanine aminotransferase (Grades ≥3)
• Increase in aspartate aminotransferase (Grades ≥3)

Uncommon

• Hyperbilirubinaemia
• Hypomagnesaemia

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¹ A case of torsade de pointes resolved spontaneously
² Fever and dyspnoea with one or more of weight gain, generalised oedema, respiratory failure or lung infiltrates. Resolved with dexamethasone

• Medicines known to cause QT/QTc interval prolongation, hypokalaemia or hypomagnesaemia
• Diuretics
• Amphotericin B
• Macrolide antibiotics
• Thioridazine
• Ziprasidone
• Pimozide
• Medicines known to cause hepatotoxic effects
• Other antileukaemic medicinal products (influence of arsenic trioxide on the efficacy of other antileukaemic medicinal products is unknown)

• Electrocardiogram (ECG)
  - Baseline: Prior to initiating therapy, a 12-lead ECG must be performed
  - During therapy: Obtained twice weekly, and more frequently for clinically unstable patients, during both the induction and consolidation phases
  - Requirement for initiation: For QTc greater than 500msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using arsenic trioxide
  - Interruption criteria: Therapy should be discontinued if the absolute QT interval is >500msec, or if syncope, rapid or irregular heart beat develops. Therapy should not resume until the QTc interval regresses to below 460msec
• Electrolytes (potassium, calcium, and magnesium)
  - Baseline: Serum electrolytes must be assessed prior to initiating therapy. Pre-existing electrolyte abnormalities should be corrected
  - During therapy: Must be monitored at least twice weekly, and more frequently for clinically unstable patients, during the induction phase. Monitored at least weekly during the consolidation phase
  - Maintenance target: Potassium concentrations should be kept above 4mmol/L and magnesium concentrations should be kept above 0.8mmol/L during therapy
• Blood glucose
  - Monitored at least twice weekly, and more frequently for clinically unstable patients, during the induction phase
• Full blood count
  - Monitored at least twice weekly, and more frequently for clinically unstable patients, during the induction phase
• Hepatic function (Bilirubin, SGOT/AST, ALT, Alkaline phosphatase, GGT)
  - Monitored at least twice weekly, and more frequently for clinically unstable patients, during the induction phase. Monitored at least weekly during the consolidation phase
• Renal function
  - Baseline: Creatinine should be assessed prior to initiating therapy
  - During Therapy: Monitored at least twice weekly, and more frequently for clinically unstable patients, during the induction phase. Monitored at least weekly during the consolidation phase
• Coagulation parameter tests
  - Monitored at least twice weekly, and more frequently for clinically unstable patients, during the induction phase

Additional Observations

• APL Differentiation Syndrome
  - Monitor for symptoms such as unexplained fever, dyspnoea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions (with or without leukocytosis)
• Peripheral neuropathy
  - Patients should be monitored periodically for symptoms or signs of neuropathy. Patients on continuing treatment may be at greater risk
• Wernicke encephalopathy/encephalopathy
  - Patients at risk of Vitamin B1 deficiency should be closely monitored for signs and symptoms of encephalopathy after arsenic trioxide initiation
• Development of second primary malignancies
  - Monitor patients for the development of second primary malignancies, as arsenic trioxide is a human carcinogen
• Vitals signs
  - Monitor for syncope, rapid or irregular heart beat. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed

Arsenic trioxide stability

• After dilution in intravenous solutions, arsenic trioxide is chemically and physically stable for 24 hours at 15°C - 30°C and 48 hours at refrigerated (2°C - 8°C) temperatures
• From a microbiological point of view, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in controlled and validated aseptic conditions

Arsenic trioxide compatibilities

• Arsenic trioxideis compatible with 5% glucose solution for injection and 0.9% sodium chloride solution for injection. See special precautions for disposal and other handling below

Special precautions for disposal of a used medicine or waste materials derived from such medicine and other handling of the product

Preparation of arsenic trioxide:

• Aseptic technique must be strictly observed throughout handling of arsenic trioxide since no preservative is present
• Arsenic trioxide must be diluted with 100 to 250ml of glucose 50mg/ml (5%) solution for injection or sodium chloride 9mg/ml (0.9%) solution for injection immediately after withdrawal from the vial
• It is for single use only, and any unused portions of each vial must be discarded properly. Do not save any unused portions for later administration
• Arsenic trioxide must not be mixed with or concomitantly administered in the same intravenous line with other medicines. Arsenic trioxide 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
• The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually for particulate matter and discoloration prior to administration
• Do not use the preparation if foreign particulate matter is present. Arsenic trioxide after reconstitution: Clear and colourless solution free of particles

Procedure for proper disposal:

• Any unused medicinal product, any items that come into contact with the product, or waste material must be disposed of in accordance with local requirements

The precise molecular and cellular mechanisms underlying the pharmacodynamics of arsenic trioxide in acute promyelocytic leukaemia (APL) are uncertain. Arsenic trioxide can induce partial differentiation and apoptosis of leukaemic cells in vitro. There is also evidence that its other known pharmacological effects (degradation of specific APL fusion transcripts, antiproliferation, inhibition of angiogenesis) may contribute to efficacy in APL.