arsenic trioxide

Trade Name:

Trisenox®

Synonym:

As2O3

Appearance:

clear, colourless solution

mixed into larger bags of fluids

Monograph Name:

arsenic trioxide

Monograph Body:

Drug Monograph

A - Drug Name

arsenic trioxide

SYNONYM(S): As₂O₃

COMMON TRADE NAME(S): Trisenox®

B - Mechanism of Action and Pharmacokinetics

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocations of the retinoic acid receptor alpha gene (RAR-α) on chromosome 17 and the promyelocytic leukemia gene (PML) on chromosome 15. The resulting fusion gene, PML–RAR-α , encodes a chimeric protein which causes an arrest of myeloid cell maturation at the promyelocyte stage of development.

The mechanism of action of arsenic trioxide is not completely understood but is likely multimodal. At lower doses, arsenic promoted cellular differentiations, while apoptosis was noted at higher concentrations.

Absorption

Peak plasma levels

2 hrs

Bioavailability

Systemic exposure (AUC) appears linear at 0.15 mg/kg.

Distribution

Widely distributed throughout tissues

PPB

Negligible

Distribution Sites

Liver, kidney and heart; to a lesser extent in lung, hair and nails. No evidence of distribution in adipose tissues.

Cross blood brain barrier?

Yes

Metabolism

Methylation in the liver to less cytotoxic metabolites, monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V). Oxidation of As^III to As^V (low plasma levels) in many tissues via enzymatic or nonenzymatic processes.

Active metabolites

As^III (primary), possibly other trivalent and pentavalent methylated metabolites

Inactive metabolites

Yes

Elimination

Urine

15% unchanged As^III; 10 - 20% MMA; 60 - 70% DMA.

Clearance

A 45% reduction in total clearance of As^III is noted with multiple dosing which may contribute to accumulation. Clearance is not dependent on body weight or dose administered at 0.15 mg/kg.

Half-life

10 - 14 hours (As^III), 32 hours for MMA^V and 70 hours for DMA^V

C - Indications and Status

Health Canada Approvals:

Acute promyelocytic leukemia (APL)

Refer to the product monograph for a full list and details of approved indications.

D - Adverse Effects

Emetogenic Potential:

Moderate

Extravasation Potential: None

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Auditory	Ear pain (8%)	E
	Tinnitus (5%)	E
Cardiovascular	Arrhythmia (5%) (including complete AV block, sudden death)	I
	Cardiotoxicity (rare)	E D
	Hypertension (10%)	I E
	Hypotension (25%)	I E
	QT interval prolonged (33%) (3% severe)	I
	Tachycardia (55%) (mild to moderate)	I
	Venous thromboembolism (<5%)	E
Dermatological	Rash (45%) (may be severe)	E
	Skin hyperpigmentation (8%)	E
Gastrointestinal	Abdominal pain (38%)	E
	Anorexia (38%)	E
	Constipation (28%)	E
	Diarrhea (63%)	E
	Dyspepsia (10%)	I E
	Nausea, vomiting (75%)	I
General	Edema (45%) (may be severe)	E
	Fatigue (68%)	E
Hematological	Disseminated intravascular coagulation (8%)	E D
	Hyperleukocytosis	E
	Myelosuppression ± infection, bleeding (13%) (severe)	E
	Other (23%) (APL differentiation syndrome)	E
Hepatobiliary	↑ LFTs (23%) (8% severe)	E
Hypersensitivity	Hypersensitivity (5%) (3% severe)	I
Injection site	Injection site reaction (23%)	I E
Metabolic / Endocrine	Abnormal electrolyte(s) (50%) (↑/↓Mg, ↑/↓K, ↓Ca, ↓PO4; 13% severe)	E
	Hyperglycemia (45%) (severe 13%)	E
	Tumor lysis syndrome (rare)	I
Musculoskeletal	Musculoskeletal pain (33%) (severe 8%)	E
Nervous System	Anxiety (33%)	E
	Depression (20%)	E D
	Dizziness (25%)	E
	Encephalopathy (rare)	E
	Headache (63%)	E
	Insomnia (43%)	E
	Paresthesia (33%) (5% severe)	E
	Seizure (8%)	E
	Somnolence (8%)	E
Ophthalmic	Blurred vision (10%)	E
	Conjunctivitis (10%)	E
Renal	Proteinuria (5%)	E
	Renal failure (8%)	E D
Respiratory	Cough, dyspnea (65%) (severe 10%)	E
	Pneumonitis (<5%)	E
Vascular	Flushing (10%)	I E
	Vasculitis (<5%)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The most common side effects for arsenic trioxide include nausea/vomiting, fatigue, cough/dyspnea, diarrhea, headache, tachycardia, abnormal electrolyte(s), leukocytosis, edema and hyperglycemia.

Since arsenic trioxide induces partial differentiation of APL cells, hyperleukocytosis may occur in some patients, but does not appear to be related to baseline white blood cell counts. Hyperleukocytosis usually resolved without additional chemotherapy treatment.

Life-threatening APL differentiation syndrome has been observed in some patients. Patients may present with dyspnea, unexplained fever, weight gain, peripheral edema, hypotension, acute renal failure, congestive heart failure and pulmonary infiltrates. Administer high-dose steroids (e.g. dexamethasone 10 mg BID) at the first signs of APL syndrome, irrespective of the leukocyte count, and continue for at least 3 days or longer until resolution. Hold arsenic trioxide treatment for patients who develop severe APL differentiation syndrome.

Most cases of elevated transaminases have been reported to resolve without interruption of treatment.

Although most cases of peripheral neuropathy are mild and moderate, some may be severe and/or irreversible.

Encephalopathy, including fatal cases, has been reported. In patients with vitamin B1 deficiency, Wernicke encephalopathy was reported after arsenic trioxide treatment. Some cases recovered with vitamin B1 supplementation.

E - Dosing

Refer to protocol by which patient is being treated.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Adults:

Do not start treatment in patients with QT/QTc > 500 msec. Correct electrolyte abnormalities and start only if QT <430 msec for males or <450 msec for females.
During treatment with arsenic trioxide, potassium concentration should be kept > 4 mmol/L and magnesium concentrations should be kept > 0.74 mmol/L.
Do not exceed the maximum number of doses recommended for the induction and consolidation treatments.
Obese patients should be dosed based on lean weight.

For induction treatment:

Intravenous: 0.15 mg/kg/day until bone marrow remission. Total induction dose should not exceed 60 doses.

For consolidation treatment:

Intravenous: 0.15 mg/kg/day for 25 doses over a period up to 5 weeks, starting 3 to 6 weeks after completion of induction therapy

Dosage with Toxicity:

Toxicity while on treatment	Action
QT/QTc > 500 msec	Hold; investigate and correct risk factors. May start if QTc < 430 msec for males and < 450 msec for females.
Syncope, rapid heart rate or arrhythmia	Hold. Monitor and correct electrolyte abnormalities. Restart when QT < 460 msec and syncope and arrhythmia resolve.
K ≤ 4mmol/L and/or Mg ≤ 0.74 mmol/L	Hold. Monitor and correct electrolyte abnormalities. Restart if Mg and K recover and no signs of arrhythmia.
Signs and symptoms of APL differentiation syndrome	Start high-dose steroids (e.g. dexamethasone 10mg IV BID) for ≥ 3 days until resolution of signs and symptoms. Hold arsenic trioxide for severe signs and symptoms.
Other grade 3 related non-hematological toxicity	Hold. Restart if recovered to baseline with a 50% dose reduction. If toxicity does not recur within 3 days, ↑ to previous dose. Discontinue if recurs.
Other grade 4 related non-hematological toxicity	Discontinue OR Hold. Restart if recovered to baseline with a 50% dose reduction. If toxicity does not recur within 3 days, ↑ to previous dose. Discontinue if recurs.

Overdose: Symptoms suggesting severe acute arsenic toxicity may include convulsions, muscle weakness and confusion. Discontinue drug, monitor ECG and consider chelation therapy. A suggested protocol for acute arsenic intoxication includes dimercaprol 3 mg/kg IM q4h until resolution of immediate life-threatening toxicity.

Dosage with Hepatic Impairment:

No clear increase in systemic exposure to arsenic trioxide or its metabolites with mild or moderate hepatic function was observed; dosage adjustment is likely not needed in mild to moderate liver impairment. Plasma metabolite levels may be increased in severe hepatic impairment; dose reduction should be considered in severe hepatic impairment (Child-Pugh C).

Hepatic impairment	Recommended dose
Mild (Child Pugh A)	0.15 mg/kg/day
Moderate (Child Pugh B)	0.15 mg/kg/day
Severe (Child Pugh C)	Consider decrease

Dosage with Renal Impairment:

Based on limited data, dosage adjustment is likely not needed in mild to moderate renal impairment. Dose reduction should be considered in severe renal impairment (CrCl < 30 mL/min) due to increased exposure and/or decreased clearance of metabolites. The use of arsenic trioxide in dialysis patients has not been studied.

Renal impairment	Recommended dose
Mild (CrCl 50 - 80 mL/min)	0.15 mg/kg/day
Moderate (CrCl 30 - 49 mL/min)	0.15 mg/kg/day
Severe (CrCl < 30 mL/min)	Consider decrease

Dosage in the elderly:

Limited data available; use with caution.

Dosage based on gender:

No information available.

Dosage based on ethnicity:

No information available.

Children:

There are no data for children < 5 years of age. Data is limited in pediatric patients (aged >5 to <18 years). Exposure is expected to be > 50% higher than that in adults; monitor patients closely. Obese pediatric patients should be dosed based on ideal body weight.

F - Administration Guidelines

Dilute dose with 100-250 mL of dextrose 5% injection or Normal Saline.
Administer IV over 1-2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed.
A central venous catheter is not required.

Do not administer in the same IV line or admix with other drugs.

Store unopened ampoules at 15-30°C. Do not freeze.

G - Special Precautions

Contraindications:

Patients who have a hypersensitivity to this drug or any of its components
Patients with QT/QTc interval > 500 msec

Other Warnings/Precautions:

Avoid concurrent use of drugs that prolong the QT interval or disrupt electrolyte levels. Pre-existing electrolyte abnormalities must be corrected before treatment with arsenic trioxide.
Exercise caution in patients with increased QT interval or who are at risk (e.g. age > 65 years, low potassium/magnesium, congenital or pre-existing QT prolongation, CHF, prior anthracycline, diabetes, autonomic neuropathy).
Exercise caution in patients with conditions that may be exacerbated by an increase in heart rate, such as tachyarrhythmias or ischemic heart disease. Patients with syncope, rapid or irregular heartbeat should be hospitalized for monitoring.
Exercise caution in patients with renal impairment, as this may result in overdose levels of the drug and may be fatal.
Obese patients may experience higher than expected plasma and tissue concentrations of arsenical species.
Poor nutritional status may decrease the capacity to methylate and detoxify arsenic. Decreased glutathione levels increase arsenic concentration and toxicity.

Other Drug Properties:

Carcinogenicity: Yes
(observed with arsenic)

Pregnancy and Lactation:

Embryotoxicity: Yes
Arsenic crosses the placental barrier.
Teratogenicity: Yes

Arsenic trioxide is contraindicated in pregnancy.
- Adequate contraception should be used by patients who can become pregnant and their partners during treatment, and for at least 6 months after the last dose.
- Adequate contraception should be used by patients who produce sperm and their partners during treatment, and for at least 3 months after the last dose.
Genotoxicity: Yes
(weak)
Clastogenicity: Yes
Lactation: Contraindicated

Arsenic is excreted in human milk; breastfeeding is contraindicated during treatment and for 3 months after the last dose.
Fertility effects: Yes

H - Interactions

AGENT	EFFECT	MECHANISM	MANAGEMENT
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc)	↑ risk of QT prolongation	Additive	Discontinue during treatment with arsenic trioxide
Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids)	↑ risk of arrhythmias	Additive	Avoid
Previous anthracycline use	↑ risk of QT prolongation	Cardiotoxic effects	Caution
Strong Pgp or MRP inhibitors	↑ arsenic exposure and/or toxicity	↓ efflux of arsenic trioxide	Caution
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors)	↓ substrate concentration and/or efficacy	↑ metabolism of CYP3A4 substrates	Caution, especially substrates with narrow therapeutic range
CYP2A substrates	↓ substrate concentration and/or efficacy	↑ metabolism of CYP2A substrates	Caution, especially substrates with narrow therapeutic range
CYP2B1/2 substrates	↓ substrate concentration and/or efficacy	↑ metabolism of CYP2B1/2 substrates	Caution, especially substrates with narrow therapeutic range

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Hospitalize patients with syncope or tachyarrhythmia.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
ECG	at baseline, twice weekly and more frequently as clinically indicated. (Consider continuous ECG monitoring for patients with risk factors for QT prolongation/torsade de pointes.)
Electrolytes (including magnesium and calcium)	At baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
Liver and renal function tests	At baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
CBC	At baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
Blood glucose levels	At baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
PT/INR	At baseline and at least twice weekly, more frequently as indicated during induction; at least weekly during consolidation
Clinical toxicity assessment for APL differential syndrome, tumour lysis syndrome, encephalopathy (especially in patients at risk of vitamin B1 deficiency), pulmonary infiltrates/effusion	Baseline and regular

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

Arsenic Trioxide - First Line Consolidation of Acute Promyelocytic Leukemia (APL)
Arsenic Trioxide - First Line Induction of Acute Promyelocytic Leukemia (APL)
Arsenic Trioxide - Relapsed_Refractory Induction of Acute Promyelocytic Leukemia (APL)
Arsenic Trioxide - Relapsed_Refractory Consolidation of Acute Promyelocytic Leukemia (APL)

K - References

Prescribing Information: Trisenox (arsenic trioxide). Cephalon (US) Inc., June 2010.

Product Monograph: Trisenox® (arsenic trioxide). Teva Canada Inc., June 7, 2019.

Product Monograph: Arsenic trioxide. Sandoz Canada Inc., June 2023.

Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19(18):3852-60.

Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998;339(19):1341-8.

Summary of Product Characteristics: Trisenox (arsenic trioxide). Cephalon (UK) Ltd., January 28, 2013.

October 2023 Modified Indications and Pregnancy/lactation sections

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

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Info Sheet Name:

arsenic trioxide (patient)

Info Sheet Introduction:

• For treating a type of leukemia called acute promyelocytic leukemia (APL)

Info Sheet Date: Vendredi, octobre 27, 2023 Info Sheet body:

Medication Information Sheet

arsenic trioxide (AR-se-nik tri-OX-ide)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Trisenox®

Appearance:

clear, colourless solution

mixed into larger bags of fluids

What is this medication for?

For treating a type of leukemia called acute promyelocytic leukemia (APL)

What should I do before I have this medication?

Tell your health care team if you have or had significant medical condition(s), especially if you have / had:

heart problems (including irregular heartbeat),
liver or kidney problems,
diabetes, or
any allergies.

Remember to:

Tell your health care team about all of the other medications you are taking.
Keep taking other medications that have been prescribed for you, unless you have been told not to by your health care team.

You will have a blood test to check for hepatitis B before starting treatment. See the Hepatitis B and Cancer Medications pamphlet for more information.

How will this medication affect sex, pregnancy and breastfeeding?

Talk to your health care team about:

How this medication may affect your sexual health.
How this medication may affect your ability to have a baby, if this applies to you.

This medication may harm an unborn baby. Tell your health care team if you or your partner are pregnant, become pregnant during treatment, or are breastfeeding.

If there is any chance you may become pregnant, you and your partner together must use 2 effective forms of birth control at the same time until at least 6 months after your last dose. Talk to your health care team about which birth control options are best for you.
If you are a patient that can get somebody pregnant, you and your partner together must use 2 effective forms of birth control at the same time until at least 3 months after your last dose. Talk to your health care team about which birth control options are best for you.
Do not breastfeed while on this medication and for 3 months after the last dose.

How is this medication given?

Arsenic trioxide is given through an IV (injected into a vein). Talk to your health care team about your treatment schedule.
If you missed your treatment appointment, talk to your health care team to find out what to do.
Each dose is usually given over 1 to 2 hours, but may last longer if reactions like flushing or dizziness happen.

What else do I need to know while on this medication?

Will this medication interact with other medications or natural health products?
- This medication can interact with other medications, vitamins, foods and natural health products. Interactions can make the treatment not work as well or cause severe side effects.
- Tell your health care team about all of your:
  - prescription and over-the-counter (non-prescription) medications and all other drugs, such as cannabis/marijuana (medical or recreational)
  - natural health products such as vitamins, herbal teas, homeopathic medicines, and other supplements
- Check with your health care team before starting or stopping any of them.
What should I do if I feel unwell, have pain, a headache or a fever?
- Always check your temperature to see if you have a fever before taking any medications for fever or pain (such as acetaminophen (Tylenol®) or ibuprofen (Advil®)).
  - Fever can be a sign of infection that may need treatment right away.
  - If you take these medications before you check for fever, they may lower your temperature and you may not know you have an infection.
How to check for fever:

Keep a digital (electronic) thermometer at home and take your temperature if you feel hot or unwell (for example, chills, headache, mild pain).
- You have a fever if your temperature taken in your mouth (oral temperature) is:
  - 38.3°C (100.9°F) or higher at any time
    
    OR
  - 38.0°C (100.4°F) or higher for at least one hour.
If you do have a fever:
- Try to contact your health care team. If you are not able to talk to them for advice, you MUST get emergency medical help right away.
- Ask your health care team for the Fever pamphlet for more information.
If you do not have a fever but have mild symptoms such as headache or mild pain:
- Ask your health care team about the right medication for you. Acetaminophen (Tylenol®) is a safe choice for most people.
- Talk to your health care team before you start taking Ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or ASA (Aspirin®), as they may increase your chance of bleeding or interact with your cancer treatment.
- Talk to your health care team if you already take low dose aspirin for a medical condition (such as a heart problem). It may still be safe to take.

What to DO while on this medication:

DO check with your health care team before getting any vaccinations, surgery, dental work or other medical procedures.
DO tell your health care team about any serious infections that you have now or have had in the past.
DO tell your health care team if you have or have had low Vitamin B1 (thiamine) levels.
DO tell your health care team if you have any new pain, numbness or tingling of your hands or feet. This is especially important if you are having trouble doing tasks (like doing up buttons, writing, walking) or if you have severe pain or numbness.
DO talk to your health care team about your risk of getting other cancers or heart problems from this treatment.

What NOT to DO while on this medication:

DO NOT smoke or drink alcohol while on treatment without talking to your health care team first. Smoking and drinking can make side effects worse and make your treatment not work as well.

What are the side effects of this medication?

The following table lists side effects that you may have when getting arsenic trioxide. The table is set up to list the most common side effects first and the least common last. It is unlikely that you will have all of the side effects listed and you may have some that are not listed.

Read over the side effect table so that you know what to look for and when to get help. Refer to this table if you experience any side effects while on arsenic trioxide.

Very Common Side Effects (50 or more out of 100 people)
Side effects and what to do	When to contact health care team
Nausea and vomiting What to look for? Nausea is feeling like you need to throw up. You may also feel light-headed. You may feel nausea within hours to days after your treatment. What to do? To help prevent nausea: It is easier to prevent nausea than to treat it once it happens. Take your anti-nausea medication(s) as prescribed, even if you do not feel like throwing up. Drink clear liquids and have small meals. Get fresh air and rest. Do not eat spicy, fried foods or foods with a strong smell. Limit caffeine (like coffee, tea) and avoid alcohol. If you have nausea or vomiting: Take your rescue (as-needed) anti-nausea medication(s) as prescribed. Ask your health care team for the Nausea & Vomiting pamphlet for more information. Talk to your health care team if: nausea lasts more than 48 hours vomiting lasts more than 24 hours or if it is severe	Talk to your healthcare team if nausea lasts more than 48 hours or vomiting lasts more than 24 hours or if it is severe.
Fatigue What to look for? Feeling of tiredness or low energy that lasts a long time and does not go away with rest or sleep. What to do? Be active. Aim to get 30 minutes of moderate exercise (you are able to talk comfortably while exercising) on most days. Check with your health care team before starting any new exercise. Pace yourself, do not rush. Put off less important activities. Rest when you need to. Ask family or friends to help you with things like housework, shopping, and child or pet care. Eat well and drink at least 6 to 8 glasses of water or other liquids every day (unless your health care team has told you to drink more or less). Avoid driving or using machinery if you are feeling tired. Ask your health care team for the Fatigue pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe.
Cough and feeling short of breath (May be severe) What to look for? You may have a cough and feel short of breath. Symptoms that commonly occur with a cough are: Wheezing or a whistling breathing Runny nose Sore throat Heartburn Weight loss Fever and chills Rarely this may be severe with chest pain, trouble breathing or coughing up blood. What to do? Check your temperature to see if you have a fever. Read the above section "What should I do if I feel unwell, have pain, a headache or a fever?". If you have a fever, try to talk to your health care team. If you are not able to talk to them for advice, you MUST get emergency medical help right away. If you have a severe cough with chest pain, trouble breathing or you are coughing up blood, get medical help right away.	Talk to your health care team. If you are not able to talk to your health care team for advice, and you have a fever or severe symptoms, you MUST get emergency medical help right away.
Diarrhea What to look for? Loose, watery, unformed stool (poo) that may happen days to weeks after you get your treatment. What to do? If you have diarrhea: Take anti-diarrhea medication if your health care team prescribed it or told you to take it. Do not eat foods or drinks with artificial sweetener (like chewing gum or ‘diet’ drinks), coffee and alcohol. Eat many small meals and snacks instead of 2 or 3 large meals. Drink at least 6 to 8 cups of liquids each day, unless your health care team has told you to drink more or less. Talk to your health care team if you can’t drink 6 to 8 cups of liquids each day when you have diarrhea. You may need to drink special liquids with salt and sugar, called Oral Rehydration Therapy. Talk to your health care team if your diarrhea does not improve after 24 hours of taking diarrhea medication or if you have diarrhea more than 7 times in one day. Ask your health care team for the Diarrhea pamphlet for more information.	Talk to your health care team if no improvement after 24 hours of taking diarrhea medication or if severe (more than 7 times in one day).
Headache; Mild joint, muscle pain or cramps (May be severe) What to look for? Mild headache New pain in your muscles or joints, muscle cramps, or feeling achy. What to do? Take pain medication (acetaminophen or opioids such as codeine, morphine, hydromorphone, oxycodone) as prescribed. Read the above section: "What should I do if I feel unwell, have pain, a headache or a fever?" before taking acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or Aspirin. These medications may hide an infection that needs treatment or they may increase your risk of bleeding. Rest often and try light exercise (such as walking) as it may help. Ask your health care team for the Pain pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe.
Fast or irregular heartbeat (May be severe) What to look for? You may have a fast or irregular heartbeat, shortness of breath, chest pain or fainting spells. What to do? Get emergency medical help right away.	Get emergency medical help right away.
Too much or too little salt in your body (May be severe) What to look for? Muscle spasms, cramping, weakness, twitching, or convulsions. Irregular heartbeat, confusion or blood pressure changes. What to do? Get emergency medical help right away for severe symptoms.	Get emergency medical help right away for severe symptoms.

Common Side Effects (25 to 49 out of 100 people)
Side effects and what to do	When to contact health care team
Higher than normal white blood cells (lymphocytes) in the blood You may have higher white blood cell levels in the blood. This can happen in the first few weeks of treatment and may last for a few weeks or months. What to look for? High white blood cell levels usually do not cause any symptoms. In severe but rare cases, you may have: fever breathing problems severe headache trouble walking fatigue What to do? Your health care team will do a blood test to check your white blood cell levels before and during your treatment. Get emergency medical help right away for severe symptoms.	Get emergency medical help right away for severe symptoms.
Swelling in your arms or legs (May be severe) What to look for? You may have mild swelling or puffiness in your arms and/or legs. Rarely, this may be severe. What to do? To help prevent swelling: Eat a low-salt diet. If you have swelling: Wear loose-fitting clothing. For swollen legs or feet, keep your feet up when sitting.	Talk to your health care team if it does not improve or if it is severe.
High blood sugar (May be severe) What to look for? You may feel thirsty. You may pee more often than usual. You may feel tired or sleepy. What to do? Your health care team may do a blood test to check your blood sugar level. You may be told to change your diet or given medication to lower your blood sugar. If you have diabetes, check your blood sugar regularly. Your health care team may ask you to check it more often than usual.	Talk to your health care team as soon as possible.
Rash; dry, itchy skin (may be severe) Darkening of the skin (rare) What to look for? You may have cracked, rough, flaking or peeling areas of the skin. Your skin may look red and feel warm, like a sunburn. Your skin may itch, burn, sting or feel very tender when touched. Your skin may turn darker than normal. What to do? To prevent and treat dry skin: Use fragrance-free skin moisturizer. Protect your skin from the sun and the cold. Use sunscreen with UVA and UVB protection and a SPF of at least 30. Avoid perfumed products and lotions that contain alcohol. Drink 6 to 8 cups of non-alcoholic, non-caffeinated liquids each day, unless your health care team has told you to drink more or less. Talk to your health care team if darkening of your skin is bothersome for you. Rash may be severe in some rare cases and cause your skin to blister or peel. If this happens, get emergency medical help right away.	Talk to your health care team if it does not improve or if it is severe.
Trouble Sleeping Your medications may cause trouble sleeping. It may get better once your body gets used to the medication or when your treatment ends. What to look for? You may find it hard to fall asleep or stay asleep. How well you sleep may change over your treatment. For example, you may have several nights of poor sleep followed by a night of better sleep. You may wake up too early or not feel well-rested after a night's sleep. You may feel tired or sleepy during the day. What to do? Talk to your health care team if it does not improve or if it is severe.	Talk to your health care team if it does not improve or if it is severe.
Pains or cramps in the belly What to look for? Pain or cramps in your belly. Constipation and diarrhea can cause pain in your belly. What to do? If the pain is severe, gets worse or doesn’t go away, talk to your health care team about other possible causes.	Talk to your health care team if it does not improve or if it is severe.
Low appetite What to look for? Loss of interest in food or not feeling hungry. Weight loss. What to do? Try to eat your favourite foods. Eat small meals throughout the day. You may need to take meal supplements to help keep your weight up. Talk to your health care team if you have no appetite. Ask your health care team for the Loss of Appetite pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe.
Mood changes What to look for? You may feel hopeless or sad most of the day. You may feel anxious, nervous, restless, agitated or stressed. You may feel like you have less energy or have little or no interest in activities that you usually enjoy. You may have changes in your personality. What to do? Eating well and exercising may give you more energy and help you feel better. Always check with your health care team before starting a new exercise program to make sure it is safe for you. Try to keep a regular bedtime routine. Go to bed and get up at the same time every day. Get support from your family, friends, community and your health care team. Talk to your health care team if your mood changes do not improve or if they are severe.	Talk to your health care team if it does not improve or if it is severe.
Neuropathy (Tingling, numb toes or fingers) (May be severe) What to look for? Numbness or tingling of your fingers and toes may happen after starting your treatment. Sometimes it can be painful and feel like burning sensation, which may be severe. What to do? Talk to your health care team if you have symptoms of neuropathy. Numbness and tingling may slowly get better after your treatment ends. In rare cases, it may continue long after treatment ends. If you continue to have bothersome symptoms, talk to your health care team for advice.	Talk to your health care team, especially if you have trouble doing tasks like doing up buttons, writing, moving, or if you have severe pain or numbness.
Constipation What to look for? Having bowel movements (going poo) less often than normal. Small hard stools (poo) that look like pellets. The need to push hard and strain to have any stool (poo) come out. Stomach ache or cramps. A bloated belly, feeling of fullness, or discomfort. Leaking of watery stools (poo). Lots of gas or burping. Nausea or vomiting. What to do? To help prevent constipation: Try to eat more fiber rich foods like fruits with skin, leafy greens and whole grains. Drink at least 6 to 8 cups of liquids each day unless your health care team has told you to drink more or less. Be Active. Exercise can help to keep you regular. If you take opioid pain medication, ask your health care team if eating more fibre is right for you. To help treat constipation: If you have not had a bowel movement in 2 to 3 days you may need to take a laxative (medication to help you poo) to help you have regular bowel movements. Ask your health care team what to do. Ask your health care team for the Constipation Pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe.
Dizziness, low blood pressure What to look for? You may feel light-headed and like you might faint (pass out). You may have nausea (feeling like you need to throw up), vomiting or blurred vision. What to do? If you feel dizzy or unwell lay down right away so that you do not fall. Try to get up and move slowly only once you feel better. Do not drive a motor vehicle or use machinery if you feel dizzy. Check your blood pressure often. Talk to your health care team to find out what a safe blood pressure is for you. Your blood pressure may drop when the medication is being given to you. Let your health care team know right away if you start to feel dizzy or lightheaded.	Talk to your health care team if it does not improve or if it is severe.

Less Common Side Effects (10 to 24 out of 100 people)
Side effects and what to do	When to contact health care team
Differentiation syndrome (May be severe) Differentiation syndrome is caused by a large, fast release of proteins (called cytokines) that help control your body’s immune system and fight disease. This is a serious side effect that usually happens within 1 to 2 weeks after starting your arsenic trioxide treatment, but it can also happen later into your treatment. If you have differentiation syndrome, it must be treated right away. What to look for? Fever, new cough, trouble breathing New swelling of arms, legs, neck, groin, or underarm area Fast weight gain, bone pain What to do? Your health care team may give you medications to treat the symptoms and they may monitor you in the hospital. If you have symptoms of differentiation syndrome, especially if they are new or severe, get emergency medical help right away.	Get emergency medical help right away.
Liver problems (May be severe) Your health care team may check your liver function with a blood test. The liver changes do not usually cause any symptoms. What to look for? Rarely, you may develop yellowish skin or eyes, unusually dark pee or pain on the right side of your belly. This may be severe. What to do? If you have any symptoms of liver problems, get emergency medical help right away.	Get emergency medical help right away.
Reactions at the injection site What to look for? Your skin may become red, itchy, bruised, and/or swollen where the injection was given. Site reactions are usually mild and go away within one to three days. What to do? Tell your nurse right away if there is any burning, stinging or other pain while arsenic trioxide is being injected into your vein. You may need to apply hot compresses or ice/cold compresses if you have mild redness or discomfort. This depends on which medication caused the reaction. Talk to your health care team to find out which treatment is right for you.	Talk to your health care team if this bothers you.
Low neutrophils (white blood cells) in the blood (neutropenia) (May be severe) When neutrophils are low, you are at risk of getting an infection more easily. Ask your health care team for the Neutropenia (Low white blood cell count) pamphlet for more information. What to look for? If you feel hot or unwell (for example if you have chills or a new cough), you must check your temperature to see if you have a fever. Do not take medications that treat a fever before you take your temperature (for example, Tylenol®, acetaminophen, Advil® or ibuprofen). Do not eat or drink anything hot or cold right before taking your temperature. You have a fever if your temperature taken in your mouth (oral temperature) is: 38.3°C (100.9°F) or higher at any time OR 38.0°C (100.4°F) or higher for at least one hour. What to do? If your health care team has told you that you have low neutrophils: Wash your hands often to prevent infection. Check with your health care team before getting any vaccines, surgeries, medical procedures or visiting your dentist. Keep a digital thermometer at home so you can easily check for a fever. If you have a fever: If you have a fever, try to contact your health care team. If you are unable to talk to the team for advice, you must get emergency medical help right away.	If you have a fever, try to contact your health care team. If you are unable to talk to the team for advice, you MUST get emergency medical help right away.
Low platelets in the blood (May be severe) When your platelets are low, you are at risk for bleeding and bruising. Ask your health care team for the Low Platelet Count pamphlet for more information. What to look for? Watch for signs of bleeding: bleeding from your gums unusual or heavy nosebleeds bruising easily or more than normal black coloured stools (poo) or blood in your stools (poo) coughing up red or brown coloured mucus dizziness, constant headache or changes in your vision heavy vaginal bleeding red or pink coloured urine (pee) What to do? If your health care team has told you that you have low platelets: Tell your pharmacist that your platelet count may be low before taking any prescriptions or over-the-counter medication. Check with your healthcare team before you go to the dentist. Take care of your mouth and use a soft toothbrush. Try to prevent cuts and bruises. Ask your health care team what activities are safe for you. Your treatment may have to be delayed if you have low platelets. Your health care team may recommend a blood transfusion. If you have signs of bleeding: If you have a small bleed, clean the area with soap and water or a saline (saltwater) rinse. Apply pressure for at least 10 minutes. If you have bleeding that does not stop or is severe (very heavy), you must get emergency medical help right away.	Talk to your health care team if you have any signs of bleeding. If you have bleeding that doesn’t stop or is severe (very heavy), you MUST get emergency help right away.
Eye problems What to look for? Your eyes may feel dry, irritated, or painful. They may look red and have a lot of tears. They may feel sensitive to light and your vision may be blurry. What to do? Avoid wearing contact lenses. Wear sunglasses with UV protection. Use protective eyewear (goggles or helmet with face mask) when playing sports, mowing the lawn or doing anything that may get particles or fumes in your eyes. You may try artificial tears (eye drops) or ointment.	Talk to your health care team as soon as possible.
Heartburn; stomach upset; bloating What to look for? Pain or burning in the middle or top part of your chest. It may get worse when you are lying down or bending over or when you swallow. A bitter or acidic taste in your mouth. What to do? Drink clear liquids and eat small meals. Do not eat acidic, fatty or spicy foods. Limit caffeine (like coffee, tea) and avoid alcohol. Avoid smoking or being around tobacco. Sit up or stand after eating. Do not lie down. Raise the head of your bed six to eight inches. You may need to use extra pillows to do this.	Talk to your health care team if it does not improve or if it is severe.
Flushing What to look for? Your face may feel warmth and the skin on your neck, upper chest, or face may quickly get red. What to do? Talk to your health care team if no improvement or if severe.	Talk to your health care team if it does not improve or if it is severe.
High blood pressure What to look for? There are usually no signs of high blood pressure. Rarely, you may have headaches, shortness of breath or nosebleeds. What to do? Check your blood pressure regularly. Your doctor may prescribe medication to treat high blood pressure. If you have a severe headache get emergency help right away as it may be a sign your blood pressure is too high.	Talk to your health care team if it does not improve or if it is severe.

Other rare, but serious side effects are possible.
If you experience ANY of the following, speak to your cancer health care provider or get emergency medical help right away:

chest pain, unusual tiredness, shortness of breath and new pain in your belly or arms
trouble seeing, speaking, or using your arms and legs
confusion, memory loss, personality changes, seizures
passing very little or no pee, or new unusual weight gain
signs of an allergic reaction: fever, itchiness, rash, swollen lips, face or tongue, chest and throat tightness, especially during or shortly after the medication is given
foamy, frothy, or bubbly-looking pee
unusual red or purple patches on your skin
muscle twitches and cramps or itchiness that won’t go away

Who do I contact if I have questions or need help?

My cancer health care provider is: ______________________________________________

During the day I should contact:________________________________________________

Evenings, weekends and holidays:______________________________________________

Other Notes:

____________________________________________________________________________

October 2023 Updated "How will this medication affect sex, pregnancy and breastfeeding" section

For more links on how to manage your symptoms go to www.cancercareontario.ca/symptoms.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

arsenic trioxide patient.pdf Info Sheet (French):

trioxyde darsenic pour le patient.pdf Monograph:

arsenic trioxide.pdf Funding Program: New Drug Funding Program Funding Instance:

Arsenic Trioxide - First Line Consolidation of Acute Promyelocytic Leukemia (APL)
Arsenic Trioxide - First Line Induction of Acute Promyelocytic Leukemia (APL)
Arsenic Trioxide - Relapsed_Refractory Induction of Acute Promyelocytic Leukemia (APL)
Arsenic Trioxide - Relapsed_Refractory Consolidation of Acute Promyelocytic Leukemia (APL)

Phonetic Spelling:

AR-se-nik tri-OX-ide

Eligibility Form:

Arsenic Trioxide - Relapsed_Refractory Induction of Acute Promyelocytic Leukemia (APL)

Arsenic Trioxide - Relapsed_Refractory Consolidation of Acute Promyelocytic Leukemia (APL)

Arsenic Trioxide - First Line Induction of Acute Promyelocytic Leukemia (APL)

Arsenic Trioxide - First Line Consolidation of Acute Promyelocytic Leukemia (APL) Cancer Type: Hematologic Leukemia - Acute Promyelocytic (APL) Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Vendredi, octobre 27, 2023 Universal Date: 2023-10-27 00:00:00 AddThis: Title URL: arsenictrioxide Drug Display Status: Active Revision Summary:
Drug Monograph: Modified Indications and Pregnancy/lactation sections
Patient Info Sheet EN: Updated "How will this medication affect sex, pregnancy and breastfeeding" section
Patient Info Sheet FR: Updated " How will this medication affect sex, pregnancy and breastfeeding" section; (Mise à jour de la section « Comment ce médicament affecte-il les relations sexuelles, la grossesse et l’allaitement?»)