ARSENIC TRIOXIDE ACCORD 1 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Arsenic Trioxide Accord 1 mg/ml Concentrate for Solution for Infusion EFG

arsenic trioxide

Read all of this leaflet carefully before this medicine is administered to you because it contains important information for you.

• Keep this leaflet, you may need to read it again.

• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience side effects, ask your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the Package Leaflet

1. What is Arsenic Trioxide Accord and what is it used for
2. What you need to know before you are given Arsenic Trioxide Accord

1. How Arsenic Trioxide Accord is administered
2. Possible side effects

1. Storage of Arsenic Trioxide Accord
2. Contents of the pack and further information

1. What is Arsenic Trioxide Accord and what is it used for

Arsenic Trioxide Accord is used in adult patients with newly diagnosed low to intermediate risk acute promyelocytic leukemia (APL), and in adult patients whose disease has not responded to other treatments. APL is a unique type of myeloid leukemia, a disease that produces abnormal white blood cells, bleeding, and bruising.

2. What you need to know before you are given Arsenic Trioxide Accord

Arsenic Trioxide Accord should be administered under the supervision of a doctor with experience in the treatment of acute leukemias.

You should not be given Arsenic Trioxide Accord

If you are allergic to arsenic trioxide or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

You should tell your doctor or nurse before you are given Arsenic Trioxide Accord, if

• you have kidney problems.
• you have any liver problems.

Your doctor will take the following precautions:

• Tests will be done to analyze the amount of potassium, magnesium, calcium, and creatinine in your blood before the first dose of Arsenic Trioxide Accord.
• You will have an electrocardiogram (ECG) before the first dose.
• Blood tests (potassium, calcium, magnesium, and liver function) will be repeated while you are being treated with Arsenic Trioxide Accord.
• In addition, you will have an electrocardiogram twice a week.

• If you are at risk of a certain type of heart rhythm disorder (e.g. ventricular tachycardia in "torsades de pointes" or QT interval prolongation), your heart will be continuously monitored.
• Your doctor may monitor your health during and after treatment, as arsenic trioxide, the active substance of Arsenic Trioxide Accord, may cause other cancers. You should report any new or unusual symptoms or circumstances whenever you visit your doctor.
• Monitoring of cognitive and motor functions if you are at risk of vitamin B1 deficiency.

Children and adolescents

Arsenic Trioxide Accord is not recommended for children and adolescents under 18 years of age.

Other medicines and Arsenic Trioxide Accord

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.

In particular, tell your doctor

• if you are taking any medicine that may cause a change in heart rhythm, including:
• • certain types of anti-arrhythmics (medicines used to correct irregular heartbeats, e.g. quinidine, amiodarone, sotalol, dofetilide)
  • medicines for treating psychosis (loss of contact with reality; e.g. thioridazine)
  • medicines for treating depression (e.g. amitriptyline)
  • certain types of medicines for treating bacterial infections (e.g. erythromycin and sparfloxacin)
  • certain medicines for treating allergies such as pollen allergy, called antihistamines (e.g. terfenadine and astemizole)
  • any medicine that causes a decrease in magnesium or potassium levels in the blood (e.g. amphotericin B)
  • cisapride (a medicine used to relieve certain stomach problems).

The effect of these medicines on the heartbeat may worsen with Arsenic Trioxide Accord. You should make sure to inform your doctor about all the medicines you are taking.

• If you are taking or have recently taken any medicine that may affect the liver. If in doubt, show the bottle or packaging to your doctor.

Using Arsenic Trioxide Accord with food and drinks

There are no restrictions on food or drink while you are receiving Arsenic Trioxide Accord.

Pregnancy

Ask your doctor or pharmacist for advice before taking any medicine.

Arsenic Trioxide Accord may harm the fetus if administered to pregnant women.

If you can become pregnant, you should use an effective method of contraception during treatment with Arsenic Trioxide Accord and for 6 months after the end of treatment.

If you are pregnant or become pregnant during treatment with Arsenic Trioxide Accord, tell your doctor.

Men should use effective contraceptive methods and be advised not to father a child during treatment with Arsenic Trioxide Accord and for 3 months after the end of treatment.

Breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Arsenic from Arsenic Trioxide Accord passes into breast milk.

As Arsenic Trioxide Accord may harm breast-fed infants, you should avoid breast-feeding while you are being treated with Arsenic Trioxide Accord and for 2 weeks after the last dose of Arsenic Trioxide Accord.

Driving and using machines

Arsenic Trioxide Accord is unlikely to affect your ability to drive or use machines.

If you experience discomfort or do not feel well after an injection of Arsenic Trioxide Accord, you should wait until the symptoms disappear before driving or using machines.

Arsenic Trioxide Accord contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per dose. This means that the medicine is essentially "sodium-free".

3. How Arsenic Trioxide Accord is administered

Duration and frequency of treatment

Patient with newly diagnosed acute promyelocytic leukemia

Your doctor will administer Arsenic Trioxide Accord once a day by infusion. In the first treatment cycle, you may receive treatment every day for up to 60 days, or until your doctor considers that your disease has improved. If your disease responds to Arsenic Trioxide Accord, you will receive 4 additional treatment cycles. Each cycle consists of 20 doses, administered 5 days a week (followed by 2 days of rest) for 4 weeks (followed by 4 weeks of rest). Your doctor will decide exactly how long you should continue treatment with Arsenic Trioxide Accord.

Patient with acute promyelocytic leukemia whose disease has not responded to other treatments

Your doctor will administer Arsenic Trioxide Accord once a day by infusion. In your first treatment cycle, you may receive treatment every day for up to 50 days, or until your doctor considers that your disease has improved. If your disease responds to Arsenic Trioxide Accord, you will receive a second treatment cycle of 25 doses, administered 5 days a week (followed by 2 days of rest), for 5 weeks. Your doctor will decide exactly how long you should continue treatment with Arsenic Trioxide Accord.

Method and route of administration

Arsenic Trioxide Accord must be diluted with a solution containing glucose or a solution containing sodium chloride.

Arsenic Trioxide Accord is usually administered by a doctor or nurse. It is administered by infusion (drip) into a vein over 1-2 hours, but the infusion may last longer if side effects such as flushing and dizziness occur.

Arsenic Trioxide Accord should not be mixed or injected with other medicines through the same tube.

If your doctor or nurse administers more Arsenic Trioxide Accord than you should

You may experience seizures, muscle weakness, and confusion. If this happens, treatment with Arsenic Trioxide Accord should be stopped immediately and your doctor will treat the arsenic overdose.

If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately if you notice any of the following side effects, as they could be signs of a serious disease called "differentiation syndrome", which can be fatal:

• difficulty breathing
• cough
• chest pain
• fever

Tell your doctor or nurse immediately if you notice any of the following side effects, as they could be signs of an allergic reaction:

• difficulty breathing
• fever
• sudden weight gain
• water retention
• fainting
• palpitations (strong heartbeat that can be felt in the chest)

While you are being treated with Arsenic Trioxide Accord, you may experience some of the following reactions:

Very common side effects (may affect more than 1 in 10 people):

• fatigue (tiredness), pain, fever, headache
• nausea, vomiting, diarrhea
• dizziness, muscle pain, numbness or tingling
• skin rash or itching, increased blood sugar, edema (swelling due to excess fluid)
• shortness of breath, palpitations, electrocardiogram abnormalities
• decreased potassium or magnesium in the blood, liver or kidney function test abnormalities, including excessive bilirubin or gamma-glutamyltransferase in the blood

Common side effects (may affect up to 1 in 10 people):

• decreased blood cell count (platelets, red blood cells, and/or white blood cells), increased white blood cell count
• chills, weight gain
• fever due to infection and low white blood cell count, herpes zoster infection
• chest pain, pulmonary bleeding, hypoxia (low oxygen level), fluid accumulation in the pericardium or lung, hypotension, heart rhythm disorder
• seizures, bone or joint pain, blood vessel inflammation
• increased sodium or magnesium, presence of ketones in blood and urine (ketoacidosis), kidney function test abnormalities, kidney failure
• stomach pain (abdomen)
• skin redness, facial swelling, blurred vision

Frequency not known (cannot be estimated from the available data):

• pulmonary infection, blood infection
• inflammation of the lungs with chest pain and difficulty breathing, heart failure,
• dehydration, confusion
• brain disease (encephalopathy, Wernicke's encephalopathy) with various manifestations, including difficulty using arms and legs, speech disorders, and confusion.

Reporting of side effects

If you experience any side effects, tell your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Arsenic Trioxide Accord

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label of the vial and on the carton.

This medicine does not require any special storage conditions.

After opening for the first time: the product should be used immediately.

Validity after dilution: Chemical and physical stability for use has been demonstrated for 168 hours at 25°C and for 2°C to 8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the storage conditions and times before use are the responsibility of the user and normally should not exceed 24 hours at 2°C-8°C, unless the dilution has been carried out under validated and controlled aseptic conditions.

After dilution, if not used immediately, the storage conditions and times before use are the responsibility of the doctor and normally should not exceed 24 hours at 2°C-8°C, unless the dilution has been carried out in a sterile environment.

Do not use this medicine if you notice any foreign particles or if the solution is discolored.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and further information

Composition of Arsenic Trioxide Accord

• The active substance is arsenic trioxide. 1 mL of concentrate contains 1 mg of arsenic trioxide. One vial contains 10 mg of arsenic trioxide.
• The other ingredients are sodium hydroxide, hydrochloric acid (for pH adjustment), and water for injection. See section 2: "Arsenic Trioxide Accord contains sodium".

Appearance and pack contents

Arsenic Trioxide Accord is a concentrate for solution for infusion. Arsenic Trioxide Accord is supplied in glass vials as a clear, colorless, sterile aqueous solution

Each carton contains 1, 5, or 10 glass vials.

Not all pack sizes may be marketed.

Marketing authorization holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6a planta,

08039 Barcelona,

Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,

95-200 Pabianice,

Poland

Or

Accord Healthcare B.V.

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

Date of last revision of this leaflet: August 2020

Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu

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This information is intended only for healthcare professionals:

STRICT ASEPTIC TECHNIQUE SHOULD BE FOLLOWED DURING HANDLING OF ARSENIC TRIOXIDE ACCORD AS IT DOES NOT CONTAIN PRESERVATIVES.

Dilution of Arsenic Trioxide Accord

Arsenic Trioxide Accord should be diluted before administration. Non-PVC plastic bags should be used.

Personnel should be properly trained to handle and dilute arsenic trioxide and should wear adequate protective equipment.

Dilution: Carefully insert the needle of a syringe into the vial through the stopper and withdraw all the contents. Arsenic Trioxide Accord should be diluted immediately after with 100 to 250 mL of injectable glucose solution 50 mg/mL (5%) or injectable sodium chloride solution 9 mg/mL (0.9%).

Unused portions of each vial will be discarded in an appropriate manner. Do not store any unused portion for later administration.

Use of Arsenic Trioxide Accord

Arsenic Trioxide Accord is for single use. It should not be mixed or administered concomitantly by the same intravenous line with other medicines.

Arsenic Trioxide Accord will be injected intravenously over 1-2 hours, but the infusion duration may be prolonged up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required.

The diluted solution should be clear and colorless. Before administration, all parenteral solutions should be visually inspected for particles and discoloration. Do not use the preparation if there are signs of particles.

After dilution in intravenous solutions, Arsenic Trioxide Accord is chemically and physically stable for 24 hours at 25°C and for 48 hours refrigerated (2-8°C). From a microbiological point of view, the product should be used immediately. If not used immediately, the storage conditions and times before use are the responsibility of the user and normally should not exceed 24 hours at 2-8°C, unless the dilution has been carried out under validated and controlled aseptic conditions.

Procedure for correct disposal

Disposal of unused medicine and all materials that have been in contact with it should be carried out in accordance with local regulations.