Consumer medicine information

Arsenic Trioxide Accord

Arsenic trioxide

BRAND INFORMATION

Brand name

Arsenic Trioxide Accord

Active ingredient

Arsenic trioxide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Arsenic Trioxide Accord.

What is in this leaflet

This leaflet answers some common questions about Arsenic Trioxide Accord. It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Arsenic Trioxide Accord against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Arsenic Trioxide Accord is used for

Arsenic Trioxide Accord is used to treat acute promyelocytic leukaemia also known as APL.

This medicine works by interfering with the growth of cancer cells and slowing their growth and spread in the body.

Your doctor may have prescribed it for another reason.

Ask your doctor if you have any questions about why Arsenic Trioxide Accord has been prescribed for you.

This medicine is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children under the age of 5 years.

Before Receiving Arsenic Trioxide Accord

When you must not be given it

You should not be given Arsenic Trioxide Accord if you have an allergy to:

  • any medicine containing arsenic or arsenic trioxide
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You should not be given this medicine if you are pregnant. It may affect your developing baby if you are given it during pregnancy.

Men and women of childbearing age must use effective birth control while they are being treated with Arsenic Trioxide Accord. Your doctor will discuss this with you.

Do not breast-feed if you are being given this medicine. The active ingredient in Arsenic Trioxide Accord passes into breast milk and there is a possibility that your baby may be affected.

You should not be given this medicine if the solution is cloudy, discoloured, turbid, or a precipitate or particles are present. The solution is normally clear and colourless.

You should not be given this medicine if, when diluted with another solution, it causes the solution to precipitate, become cloudy, turbid, discolour, or particles are visible.

You should not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If you are given this medicine after the expiry date has passed, it may not work as well.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • low levels of potassium or magnesium in the body (electrolyte imbalance)
  • congestive heart failure
  • rapid or irregular heartbeat
  • liver problems
  • a history of kidney problems.

Tell your doctor if you are pregnant, plan to become pregnant or breast feeding. Your doctor can discuss with you the risks and benefits involved in using Arsenic Trioxide Accord.

Pregnancy tests should be done in women of childbearing age prior to the treatment with Arsenic Trioxide Accord.

If you have not told your doctor about any of the above, tell him/her before you are given Arsenic Trioxide Accord.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket, health food shop, naturopath or herbalist.

Some medicines and Arsenic Trioxide Accord may interfere with each other.

These include:

  • fluid or water tablets (diuretics)
  • some medicines used to treat fungal infections such as amphotericin B
  • medicines which affect heart rhythm (prolong the Q-T interval) for example:
    - some antibiotics e.g. erythromycin
    - antipsychotics e.g. thioridazine
    - some types of antiarrhythmics e.g. quinidine
    - antidepressants e.g. amitriptyline
    - some antihistamines e.g. terfenadine.

Ask your doctor for more information on which medicines to be careful with or avoid while using Arsenic Trioxide Accord.

These medicines may be affected by Arsenic Trioxide Accord or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while being given this medicine.

How Arsenic Trioxide Accord is given

Arsenic Trioxide Accord must only be given by a doctor or nurse under the supervision of a doctor experienced in managing patients with acute leukaemia.

Arsenic Trioxide Accord is diluted and then given as a slow injection into a vein.

Your doctor will decide what dose of Arsenic Trioxide Accord you will receive and how long you will receive it. This depends on your medical condition and other factors, such as your weight.

If you receive too much (overdose)

Arsenic Trioxide Accord must only be given by a doctor or nurse so an overdose is not likely to occur. Contact your doctor if you are concerned about the dose.

Symptoms of an overdose are similar to side effects but are more severe and are listed under Side Effects below.

While you are given Arsenic Trioxide Accord

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you have been given Arsenic Trioxide Accord.

Tell any other doctors, dentists, and pharmacists who treat you that you have been given this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you have been given this medicine. It may affect other medicines used during surgery.

If you become pregnant while being given this medicine, tell your doctor immediately.

Men and women of childbearing age should take effective birth control precautionary method while they are being treated with Arsenic Trioxide Accord.

If you are about to have any blood tests, tell your doctor that you are being given this medicine. It may interfere with the results of some tests.

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how Arsenic Trioxide Accord affects you. This medicine may cause dizziness, tiredness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side Effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Arsenic Trioxide Accord.

This medicine helps most people with APL, but it may have unwanted side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • tiredness
  • fever
  • nausea , vomiting, diarrhoea, stomach pain, sore mouth
  • bleeding or bruising more easily than usual
  • sore throat
  • cough
  • difficulty breathing
  • headache
  • difficulty sleeping
  • fast heart beat
  • skin rash, itching
  • bone or joint pain
  • numbness, aching or weakness of the arms and legs or other muscles
  • tingling in the hands and feet
  • fits or convulsions
  • mood changes
  • liver dysfunction, abnormal liver enzymes
  • low potassium levels
  • low white blood cell and platelet count
  • bleeding, blood clot
  • infection
  • signs of hyperglycaemia (high blood sugar):
    - large amounts of urine
    - excessive thirst
    - dry mouth and skin.

The above list includes serious side effects that may require medical attention. The above list includes the most common side effects of your medicine.

If any of the following happen, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

  • chest pain
  • difficulty or pain when breathing
  • stroke
  • passing little or no urine
  • signs of APL differentiation syndrome as listed below:
    - unexplained fever
    - shortness of breath, difficulty breathing
    - and/or weight gain.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation .

Tell your doctor or nurse if you notice any other effect that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects, for example, change in number of white blood cells can only be found when your doctor does tests from time to time to check your progress.

Storage

Arsenic Trioxide Accord will be stored in the surgery, pharmacy or ward of a hospital. The injection is kept in a cool dry place where the temperature stays below 30°C.

Once diluted the solution should be used as soon as possible. It is a sterile solution for single use. If storage is necessary the prepared solution should be refrigerated between 2°C and 8°C and stored for no longer than 24 hours before discarding.

Product Description

What it looks like

Arsenic Trioxide Accord is a clear colourless solution in a vial. It is available in packs of 1, 5 or 10.

Ingredients

Active Ingredient:
Arsenic trioxide

Inactive Ingredients:
Sodium hydroxide
Hydrochloric acid
Water for injections

This medicine does not contain lactose, sucrose, gluten, tartrazine, or other azo dyes or preservatives.

Name and Address of the Sponsor

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

Australian Register numbers

10 mg10 mL: AUST R 324603

Date of Preparation

This leaflet was prepared on 20 October 2020..

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Arsenic Trioxide Accord

Active ingredient

Arsenic trioxide

Schedule

S4

 

1 Name of Medicine

Arsenic trioxide.

2 Qualitative and Quantitative Composition

1 mL contains 1 mg arsenic trioxide.
1 vial of 10 mL concentrated injection contains 10 mg arsenic trioxide.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Arsenic Trioxide Accord is a clear, colourless, concentrated injection for infusion Arsenic Trioxide Accord must be diluted before use.

4 Clinical Particulars

4.1 Therapeutic Indications

For the induction of remission and consolidation in patients with acute promyelocytic leukaemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterised by the presence of the t(15:17) translocation or PML/RAR-alpha gene expression.
For the induction of remission and consolidation in patients with previously untreated acute promyelocytic leukaemia (APL) in combination with all-trans retinoic acid (ATRA) and/or chemotherapy and whose APL is characterised by the presence of the t(15:17) translocation or PML/RAR-alpha gene expression.

4.2 Dose and Method of Administration

Arsenic Trioxide Accord must be diluted before use.

Method of administration.

0.15 mg/kg/day diluted with 100 - 250 mL of 5% glucose injection or 0.9% sodium chloride injection and administered intravenously (IV) over two hours.
Cycles of treatment are given to achieve complete remission, 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 Accord 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 Accord may be given in combination with all-trans-retinoic acid (ATRA) and/or chemotherapy. Dosage regimens for high risk patients and low to intermediate risk patients are described in Table 1 and Table 2 respectively.
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.
It is strongly recommended that during induction patients are treated with prednisone (or prednisolone); 1 mg/kg/day for at least 10 days. Aggressive platelet and plasma support should also be considered to maintain haemostatic targets.
For patients in CR after the 3 cycles of induction/consolidation maintenance consisting of ATRA from Day 1-14, followed by 6-mercaptopurine (6MP) and methotrexate (MTX) both from Day 15-90 (each cycle 3 months) may then be administered for 24 months.
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.

Dose modification in newly diagnosed/de novo APL patients.

See Section 4.4 Special Warnings and Precautions for Use.

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

Induction treatment therapy.

For induction, a daily infusion of 0.15 mg/kg/day is continued 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 may begin 3-4 weeks after completion of the induction cycle. The dose is the same as for induction, except that 25 daily doses over a period of up to 5 weeks are given.
There are no data on the use of arsenic trioxide in patients with renal and hepatic impairment. Caution is recommended in renal impairment since renal excretion is the main route of elimination of arsenic trioxide. Caution is also required in hepatic impairment since the liver is the major site of detoxification of arsenic trioxide.

Dose modification in refractory to, or relapsed from retinoid and anthracycline therapy.

Treatment with Arsenic Trioxide Accord 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.

Drug stability.

Once diluted the solution should be used as soon as possible. It is a sterile solution for single use in one patient only and contains no antimicrobial preservative. If storage is necessary the prepared solution should be refrigerated between 2°C and 8°C and stored for no longer than 24 hours before discarding. Only a clear solution without any particles should be used.

Drug compatibilities.

Arsenic Trioxide Accord is compatible with 5% glucose injection and 0.9% sodium chloride injection.

Protective measures.

Arsenic trioxide must be handled with care. The following protective recommendations are given due to the toxic nature of this substance:
personnel should be trained in good handling technique;
pregnant staff should be excluded from working with this medicine;
personnel handling arsenic trioxide should wear protective clothing: goggles, gowns and disposable gloves and masks;
a designated area should be defined for preparation (preferably under a laminar flow system) with the work surface protected by disposable, plastic-backed, absorbent paper;
all items used for administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration;
accidental contact with the skin or eyes should be treated immediately with copious amounts of water and medical attention should be sought.

4.3 Contraindications

Arsenic trioxide is contraindicated in patients who are hypersensitive to arsenic or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Arsenic trioxide should be administered under the supervision of a physician experienced in the management of patients with acute leukaemia.

APL differentiation syndrome.

Some patients with APL treated with arsenic trioxide experience symptoms similar to a syndrome called retinoic acute promyelocytic leukaemia (RA-APL) syndrome or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions with or without leukocytosis. This syndrome can be fatal. The first signs that could suggest the development of the APL differentiation syndrome are unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities. The management of the syndrome has not been fully studied, but high dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms.
In APML4, an obligatory part of the treatment protocol was use of prednisone or prednisolone, 1 mg/kg/day, on days 1-10, and beyond day 10 if WCC was elevated > 10 x 109/L or if there were signs of APL differentiation syndrome. The APML4 study protocol included APL differentiation syndrome as the most serious and potentially fatal side effect of ATRA. Whenever the features of APL differentiation syndrome developed, ATRA and/or arsenic trioxide doses were temporarily ceased or reduced. When it was time to restart ATRA and/or arsenic trioxide therapy the dose of ATRA was reduced to 25 mg/m2/day for 14 days and the dose of arsenic trioxide was reduced to 0.08 mg/kg/day. In particular, the compulsory use of prednisone (or prednisolone) as prophylactic therapy and the delayed introduction of arsenic trioxide on day 9 of the induction therapy was expected to almost completely eliminate the severest form of APL differentiation syndrome.
In Lo-Coco trial, prednisone at a dose of 0.5 mg/kg/day was administered from day 1 until the end of induction therapy as a prophylaxis therapy for APL differentiation syndrome. Where features of APL differentiation syndrome occurred, the dose of arsenic trioxide was reduced to 0.08 mg/kg/day or ceased temporarily and ATRA was ceased depending on clinical severity. Dexamethasone, 10 mg every 12 hours iv was promptly started until the signs and symptoms of APL differentiation syndrome had disappeared for a minimum of 3 days. Furosemide was given when clinically required. As soon as the symptoms of APL differentiation syndrome disappeared and the patients' clinical conditions improved, the treatment with ATRA and/or arsenic trioxide was resumed at 50% of the previous dose for the first 7 days. Thereafter, in the absence of worsening of the previous toxicity, ATRA and/or arsenic trioxide was resumed at full dosage. Whenever the APL differentiation syndrome symptoms reappeared, ATRA and arsenic trioxide doses were reduced as described above.

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. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-depleting diuretics, or other conditions that result in hypokalaemia or hypomagnesaemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.

QT/QTc prolongation.

QT prolongation should be expected during treatment with arsenic trioxide and torsades de pointes as well as complete heart block has been reported. Over 460 ECG tracings from 40 patients with refractory or relapsed APL treated with arsenic trioxide were evaluated for QTc prolongation. Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after arsenic trioxide infusion, and then returned towards baseline by the end of 8 weeks after arsenic trioxide infusion. In these ECG evaluations, women did not experience more pronounced QT prolongation than men, and there was no correlation with age.

Complete AV block.

Complete AV block has been reported with arsenic trioxide in the published literature including a case of a patient with APL.

ECG and electrolytes: monitoring recommendations.

Patients with congestive heart failure should not be administered arsenic trioxide, except when the benefit outweighs the risk. Prior to initiating therapy with arsenic trioxide, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium and magnesium) and creatinine should be assessed; pre-existing electrolyte abnormalities should be corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using arsenic trioxide. During therapy with arsenic trioxide, potassium concentrations should be kept above 4 mmol/L and magnesium concentrations should be kept above 0.8 mmol/L. Patients who reach an absolute QT interval > 500 msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending arsenic trioxide therapy should be considered. If syncope, rapid or irregular heart beat develops, the patient should be hospitalised for monitoring and serum electrolytes should be assessed. Arsenic trioxide therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion.

Peripheral neuropathy.

Peripheral neuropathy has been associated with the use of arsenic trioxide. In the largest case series (Soignet SL, 2001; see Section 5.1 Pharmacodynamic Properties, Clinical trials) one patient (out of 40) experienced grade 3 neuropathy and required discontinuation of arsenic trioxide treatment. Patients should be monitored periodically for symptoms or signs of neuropathy. Patients on continuing arsenic trioxide treatment may be at greater risk.

Hepatotoxicity.

During the APML4 study, the dose of arsenic trioxide was decreased to 0.08 mg/kg/day for grade 3 hepatotoxicity and temporarily discontinued for grade 4 hepatotoxicity. After temporary discontinuation arsenic trioxide was restarted at 0.08 mg/kg/day when the liver function test (LFT) improved to grade 2 or better. If no further deterioration occurred in the LFT after one week, the arsenic trioxide dose was increased back to 0.15 mg/kg/day.
The Lo-Coco et al, 2013 clinical trial defined hepatotoxicity as an increase in serum bilirubin and/or serum glutamic oxaloacetic transaminase (SGOT) and/or alkaline phosphatase > 5 times the normal upper level. Hepatotoxicity was managed with temporary discontinuation and subsequent dose adjustment of ATRA and/or arsenic trioxide. As soon as serum bilirubin and/or SGOT and/or alkaline phosphatase decreased to below 4 times the normal upper level, treatment with ATRA and/or arsenic trioxide was resumed at 50% of the preceding daily dose during the first 7 days. Thereafter, in the absence of worsening of the previous toxicity, ATRA and/or arsenic trioxide was resumed at the normally prescribed dosage. In case of reappearance of hepatotoxicity, ATRA and/or arsenic trioxide were permanently discontinued.

Hyperleukocytosis.

Arsenic trioxide has been investigated in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen, in an open-label, single-arm, non-comparative study (Soignet SL, 2001). Patients received arsenic trioxide 0.15 mg/kg/day intravenously over 1 to 2 hours daily until the bone marrow was cleared of leukaemic cells or up to a maximum of 60 days. In this study in relapsed or refractory APL patients, treatment with arsenic trioxide was associated with the development of hyperleukocytosis (≥ 10 x 109/L) in some patients. There did not appear to be a relationship between baseline white blood cell (WBC) counts and development of hyperleukocytosis nor did there appear to be a correlation between baseline WBC count and peak WBC counts. Hyperleukocytosis 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 109/L, except in one patient who had a WBC count of 22 x 109/L during consolidation. Twenty patients (50%) experienced leukocytosis; however, in all these patients, the WBC count was declining or had normalised by the time of bone marrow remission and cytotoxic chemotherapy or leukopheresis was not required.
In APML4 three de novo APL patients demonstrated marked hyperleukocytosis when treated with arsenic trioxide combination therapy. Hyperleukocytosis regressed following anthracycline administration, no major complications were observed. As a safeguard against hyperleukocytosis, prednisone (or prednisolone) 1 mg/kg/day was instituted on day 1 for at least 10 days in all patients. Prednisone was continued until the WCC fell below 10 x 109/L.
In de novo APL the Lo-Coco trial reported leukocytosis during induction therapy in 35 of 74 patients in the ATRA with arsenic trioxide group (47%) and in 19 of 79 patients in the ATRA with chemotherapy group (24%) (P = 0.007). All cases were successfully managed with hydroxyurea after treatment initiation at the dosage of 500 mg/qid for WBC between 10 and 50 x 109/L, and 1.0 g/qid for WBC > 50 x 109/L. Hydroxyurea was discontinued when WBC count decreased to < 10 x 109/L.

Use in hepatic impairment.

Safety and effectiveness of arsenic trioxide in patients with hepatic impairment have not been studied.

Use in renal impairment.

Safety and effectiveness of arsenic trioxide in patients with renal impairment have not been studied. Particular caution is needed in patients with renal failure receiving arsenic trioxide, as renal excretion is the main route of elimination of arsenic.

Use in the elderly.

There is limited clinical data on the use of arsenic trioxide in the elderly population. Elderly patients have a greater risk of reduced renal function. Because renal excretion is the main route of elimination of arsenic, particular caution is needed in these patients.

Paediatric use.

There are limited clinical data on the paediatric use of arsenic trioxide. Of 5 patients below the age of 18 years (age range: 5 to 16 years) who received a dose of 0.15 mg/kg/day for relapsed/refractory APL, 3 achieved a complete response. In two published studies in children with de novo APL (age range 5 - 15 years; 11 and 19 children respectively) treated with single agent arsenic trioxide, 89.5% and 91.0% of the children achieved CR, with overall response reaching 91% at 30 months and 84% at 5 years respectively.
Safety and effectiveness in paediatric patients below the age of 5 years has not been studied.

Effects on laboratory tests.

The patient's electrolyte, haematologic and coagulation profiles should 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.
ECGs should be obtained weekly, and more frequently for clinically unstable patients, during induction and consolidation.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No assessments of drug interactions have been made. Caution is advised when arsenic trioxide is used with medications that:
can prolong the QT interval (e.g. certain antiarrhythmics, thioridazine);
lead to electrolyte abnormalities (e.g. diuretics, amphotericin B).
Arsenic trioxide should not be used concomitantly with ziprasidone or pimozide because of potential additive effects on prolongation of the QT intervals.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of arsenite on fertility have not been systematically studied. Men and women of childbearing potential must use effective contraception during treatment with arsenic trioxide.
(Category X)
Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy.
Arsenic trioxide should not be given to patients who are pregnant. Pregnancy test prior to the treatment with arsenic trioxide should be considered.
In hamsters, rats and mice, parenteral administration of arsenite during the period of organogenesis produces malformations, including neural tube, eye, facial, genitourinary and skeletal defects, at respective single doses of ca 2-13 fold the clinical dose on a body surface area basis; no-effect dose levels were not established. Arsenite treatment of mice during gestation has also produced a widespread tumorigenic response in offspring. The effects of arsenic trioxide injection on human pregnancy are not known, but the results of the animal studies indicate that this treatment should not be given to pregnant women.
 It is not known whether arsenite and/or its metabolites are excreted in milk. Arsenic trioxide should not be administered to lactating women.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Death.

Sudden death, sometimes early in the treatment with arsenic trioxide has occurred. Autopsies have sometimes failed to identify a cause of sudden death. Cerebral haemorrhage has been the cause of death in three patients. Another patient on whom an autopsy was not performed became asystolic and died while on continuous cardiac telemetry. The level of arsenic trioxide excreted in the urine does not seem to be related as a cause of death. Adverse reactions are ranked using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000). See Table 3.
Seven relapsed and/or refractory APL patients treated with arsenic trioxide developed polyneuropathy compatible with chronic arsenic toxicity while in maintenance therapy and one had marked distal muscular atrophy (Huang et al, 1998). Reactions are often mild and there may be no need to interrupt arsenic trioxide therapy. Adverse effects usually resolve after therapy is completed.
While all the newly diagnosed/de novo APL patients experienced AEs in the APML4 trial, the majority of these AEs were related to the prescribed protocol treatment and were expected. Ninety one of the 124 patients commencing induction treatment (73%) experienced SAEs and 69% experienced more than 1 SAE.
Within the clinical setting of APL, and based on the protocol prescribed chemotherapy regimen, changes to laboratory parameters were both expected and manageable. No unexpected or new laboratory abnormalities were noted, and patients were clinically managed according to the usual practice of each clinical trial site. Overall, patients tolerated the APML4 protocol prescribed regimen. The use of an aggressive haemostatic/blood product support protocol during the induction cycle contributed to a reduction in fatal haemorrhage, and the use of obligatory corticosteroids may have contributed to the absence of APL differentiation syndrome-associated early deaths.
In the Lo-Coco trial, ATRA + arsenic trioxide combination resulted in more frequent prolongation of the QTc interval and liver function abnormalities. Hepatotoxic effects appeared to be manageable with temporary discontinuation of the study medication and subsequent dose adjustments; the use of hydroxyurea was sufficient to counteract hyperleukocytosis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Treatment of overdose.

If symptoms of serious acute arsenic toxicity appear, the drug should be immediately discontinued and chelation therapy should be considered. Other anti-arsenical treatment may be considered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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, anti-proliferation, inhibition of angiogenesis) may contribute to efficacy in APL.

Clinical trials.

In relapsed or refractory APL.

Studies using arsenic trioxide in APL commenced in the early 1990s in China. In 1997 the first studies were undertaken in the US in the treatment of APL resistant to all-trans retinoic acid (ATRA, Australian approved name, Tretinoin) and anthracycline therapy. Six case series in 115 patients provide the best evidence for the efficacy of arsenic trioxide in APL that have relapsed or are refractory to ATRA, with or without an anthracycline. See Table 4.
In the majority of studies the complete remission rate is greater than 85%. The remission rate reduces over time and the results vary.

In previously untreated/de novo APL.

APML4.

In Australia, the Australasian Leukaemia and Lymphoma Group (ALLG) conducted the APML4 study, an open-label phase 2, multicentre trial in 124 patients including 4 children (only) with de novo APL were studied from 2004 to 2009. The median age of patients was 44 years. 19% of the enrolled patients were in high risk category; 54% were in the intermediate risk category 27% were in low risk category as defined by Sanz risk stratification. The APML4 study did not have a control arm but used the historical comparison of the APML3 study with ATRA and chemotherapy. Arsenic trioxide was administered at 0.15 mg/kg/day (for detailed dosage regimen, see Section 4.2 Dose and Method of Administration).
The primary objectives of APML4 were to evaluate the effect of a chemotherapy protocol consisting of arsenic trioxide added to standard induction (ATRA plus intensive idarubicin) with two cycles of consolidation with ATRA plus arsenic trioxide on the time to relapse; and to assess the effect of obligatory use of prednisone (or prednisolone) and aggressive haemostatic support, during induction on the early death rate.
124 (62 female and 62 male) patients were evaluable for assessment of the CR rate. 112/124 (90.3%) completed induction and a further 4/124 did not complete induction but attained complete remission. All 112 patients who completed induction achieved molecular CR by the end of the 2nd consolidation cycle (CON2). 88% of these 112 patients completed all 8 maintenance cycles. The observed CR rate was 93.5% (95% CI: 87.9% - 97.2%). Of 112 patients evaluable for time to relapse analyses, 4 suffered molecular relapse and 1 suffered haematological relapse. The observed annual relapse-free rates measured from the end of CON2 were as follows: 1 and 2 years 97.3% (95% CI: 91.8% - 99.1%); 3, 4 and 5 years 95.4% (95% CI: 89.3% - 98.1%). The observed overall survival rates were as follows: 1 year 96.0% (95% CI: 90.6% - 98.3%); 2, 3, 4 and 5 years 94.3% (95% CI: 88.5% - 97.3%). The observed event-free survival rates were as follows: 1 year 88.7% (95% CI: 81.7% - 93.1%); 2 years 87.9% (95% CI: 80.7% - 92.5%); 3, 4 and 5 years 86.1% (95% CI: 78.6% - 91.1%).
One of the primary endpoints 'early death' rate in APML3 was 7.1% (5 of 70) and in APML4 it was 3.2% (4 of 124 patients); this difference was not statistically significant (OR= 0.44; 95% CI: 0.08 to 2.10; P = 0.29). The cause of death in 2 of the 4 in APML4 and 7 of the 8 in APML3 was haemorrhage Therefore there appears to be a smaller number of deaths linked to haemorrhage in APML4, in which obligatory corticosteroids and aggressive haemostatic support were provided during the induction phase.

Lo-Coco et al, 2013 (Lo-Coco).

The Lo-Coco, open-label, comparative, multi-centre, randomised phase 3 study aimed to show non-inferiority of ATRA + arsenic trioxide, for induction and consolidation relative to ATRA + chemotherapy. 162 patients with newly diagnosed, low-to-intermediate risk APL were studied from October 2007 to September 2010 with a median follow up of 34.4 months (range, 0.5 to 55.8). The comparator arm of this study included a low dose chemotherapy and ATRA regimen as maintenance therapy. The Intention-to-treat analysis (ITT) was in 156 (80 female and 76 male) patients. Median age of patients included in the study was 45 years.
Of the 150 evaluable patients, 97% in the ATRA + arsenic trioxide group (72 of 74) were alive and free of events at 24 months, as compared with 86% in the ATRA + chemotherapy group (65 of 76) (difference, 11% 95% CI: 2 to 22). The observed advantage in the 2-year event-free survival (which was the primary efficacy endpoint) with ATRA + arsenic trioxide compared to ATRA + chemotherapy (97% vs 86%) appears to be due mainly to lower mortality from causes other than relapse, probably as a consequence of reduced severe hematologic toxicity together with similar anti-leukaemic efficacy. The study reported haematological CR in all (100%) ATRA + arsenic trioxide patients after a median 32 days of induction.
Both the Lo-Coco and APML4 studies used arsenic trioxide at a dose of 0.15 mg/kg/day however, in the Lo-Coco study idarubicin was omitted from the induction therapy and ATRA and arsenic trioxide were used in an extended consolidation therapy period of 28 weeks. The Lo-Coco dosage regimen also omitted the 2 year maintenance therapy consisting of ATRA + 6-mercaptopurine (6MP) ± methotrexate (MTX) utilised in the APML4 regimen.

5.2 Pharmacokinetic Properties

Absorption.

Following an initial dose of 10 mg intravenously over two hours, peak plasma levels of total arsenic range from 5.54 to 7.30 micromoles of arsenic/L at 0.9 hours. Continuous administration of arsenic trioxide over a period of thirty days does not alter the pharmacokinetic behaviour. Increased amounts of arsenic appeared in the urine.

Distribution.

Arsenic trioxide given by intravenous injection is rapidly distributed. In the blood, arsenic trioxide diffuses from plasma into red blood cells and 95-97% is bound to haemoglobin. Arsenic trioxide is distributed into sulphur rich tissues such as bone marrow, hair, nails and skin where it accumulates with repeated dosing.

Metabolism.

The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases. The main site of methylation reactions appears to be the liver. Arsenic is stored mainly in liver, kidney, heart, lung, hair and nails.
In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11.

Excretion.

The metabolites monomethylarsonic acid, dimethylarsinic acid and arsenite are mainly excreted in the urine. Arsenic is excreted in the urine with a daily excretion accounting for approximately 1% to 8% of the total daily dose administered but may range higher. Urinary excretion continues after withdrawal of the drug although the amount excreted is decreased. Studies with radiolabelled arsenic trioxide have demonstrated that after oral administration of 0.06 ng arsenic, approximately 60% of the radioactivity was recovered in the urine within 8 days.
The mean plasma elimination t1/2 value in patients receiving arsenic trioxide was 92 hours. This 92-hour plasma elimination half-life is consistent with the reported 3 to 5 day urinary excretion half-life for arsenic.
Arsenic trioxide content in hair and nails increases gradually during therapy and the concentrations may reach 2.5 to 2.7 microgram per gram of tissue at complete remission which is five to seven times that before treatment. The content of arsenic in hair and nails decreases following cessation of treatment.

5.3 Preclinical Safety Data

Genotoxicity.

Positive findings have been observed with arsenite in genotoxicity assays, including gene mutation in mammalian cells, clastogenicity in vitro and in vivo, and cell transformation. Positive genotoxicity findings have also been reported for the human metabolite dimethylarsinic acid (DMA).

Carcinogenicity.

Epidemiological studies have found considerable evidence for an association between arsenic exposure and increased incidence of tumours, especially of the skin, lung and some internal organs. The mechanism of action is not fully understood, but it is likely to involve carcinogenic methylated metabolites such as dimethylarsinic acid (DMA). Arsenite treatment of mice during gestation has produced a widespread tumorigenic response in offspring.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium hydroxide, hydrochloric acid, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Arsenic Trioxide Accord is available in one strength, 10 mg/10 mL, in Type I glass vials in packs of 1, 5 or 10.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Proper safe handling and disposal relevant to cytotoxic drugs should be observed by medical staff.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1327-53-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.