Patient Information Leaflet

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

arsenic trioxide

Read this leaflet carefully before you start using this medicine because it contains important information for you.

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

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

1. How to take Trioxide Arsenic Accord
2. Possible side effects

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

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

Trisodium arsenite Accord should be administered under the supervision of a doctor experienced in the treatment of acute leukemias.

Do not receive Trisodium arsenite Accord

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

Warnings and precautions

You should consult your doctor or nurse before receiving Trisodium arsenite Accord if

• You have kidney failure.
• You have any liver problems.

Your doctor will take the following precautions:

• Blood tests will be performed to analyze the levels of potassium, magnesium, calcium, and creatinine in your blood before the first dose of Trisodium arsenite Accord.
• You will need to have an electrocardiogram (ECG) before the first dose.
• Blood tests (potassium, calcium, magnesium, and liver function) will be repeated while you continue treatment with Trisodium arsenite Accord.
• Additionally, you will have an electrocardiogram twice a week.

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

Children and adolescents

Trisodium arsenite Accord is not recommended for children or adolescents under 18 years old.

Other medications and Trisodium arsenite Accord

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication, including those purchased without a prescription.

In particular, inform your doctor

• If you are taking any medication that can cause a change in heart rhythm, including:
• • Some types of antiarrhythmics (medications used to correct irregular heartbeats, e.g. quinidine, amiodarone, sotalol, dofetilide)
  • Medications to treat psychosis (loss of contact with reality; e.g. thioridazine)
  • Medications to treat depression (e.g. amitriptyline)
  • Some types of medications to treat bacterial infections (e.g. erythromycin and ciprofloxacin)
  • Some medications to treat allergies such as pollen allergy, called antihistamines (e.g. terfenadine and astemizole)
  • Any medication that produces a decrease in the level of magnesium or potassium in the blood (e.g. amphotericin B)
  • Cisapride (medication used to alleviate certain stomach problems).

The effect of these medications on heart rhythm may worsen with Trisodium arsenite Accord. You should ensure that you inform your doctor about all the medications you take.

• If you are taking or have taken recently any medication that can affect the liver. If you are unsure, show the bottle or packaging to your doctor.

Use of Trisodium arsenite Accord with food and beverages

There are no restrictions on food or beverages while receiving Trisodium arsenite Accord.

Pregnancy

Consult your doctor or pharmacist before using any medication.

Trisodium arsenite Accord may cause harm to the fetus if administered to pregnant women.

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

If you become pregnant or become pregnant during treatment with Trisodium arsenite Accord, consult your doctor.

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

Lactation

Consult your doctor or pharmacist before using any medication.

Arsenic in Trisodium arsenite Accord passes into breast milk.

As Trisodium arsenite Accord may harm infants, avoid breastfeeding while on treatment with Trisodium arsenite Accord and for two weeks after the last dose of Trisodium arsenite Accord.

Driving and operating machinery

It is expected that the influence of Trisodium arsenite Accord on your ability to drive and operate machinery will be negligible or insignificant.

If you experience discomfort or do not feel well after an injection of Trisodium arsenite Accord, you should wait for the symptoms to subside before driving or operating machinery.

Trisodium arsenite Accord contains sodium

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

Treatment Duration and Frequency

Patients with Newly Diagnosed Acute Promyelocytic Leukemia

Your doctor will administer Trióxido de Arsénico Accord once a day through infusion. In the first treatment cycle, you may receive treatment every day for up to 60 days, or until your doctor considers your condition to have improved. If your condition responds to Trióxido de Arsénico Accord, you will receive an additional 4 treatment cycles. Each cycle consists of 20 doses, which will be 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 Trióxido de Arsénico Accord.

Patients with Acute Promyelocytic Leukemia Whose Condition Has Not Responded to Other Treatments

Your doctor will administer Trióxido de Arsénico Accord once a day through infusion. In your first treatment cycle, you may receive treatment every day for up to 50 days, or until your doctor considers your condition to have improved. If your condition responds to Trióxido de Arsénico Accord, you will receive a second treatment cycle of 25 doses, which you will receive 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 Trióxido de Arsénico Accord.

Form and Route of Administration

Trióxido de Arsénico Accord must be diluted with a solution containing glucose or a solution containing sodium chloride.

Trióxido de Arsénico Accord is usually administered by a doctor or nurse. It is administered through an infusion set inserted into a vein for 1-2 hours, but the infusion may last longer if side effects such as hot flashes and dizziness occur.

Trióxido de Arsénico Accord should not be mixed or injected through the same tube with other medications.

If Your Doctor or Nurse Administers More Trióxido de Arsénico Accord Than Prescribed

You may experience seizures, muscle weakness, and confusion. If this occurs, treatment with Trióxido de Arsénico Accord should be stopped immediately, and your doctor will treat the arsenic overdose.

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

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

Inform your doctor or nurse immediately if you notice one of the following side effects, as they may be signs of a serious disease called “differentiation syndrome,” which could be fatal:

• difficulty breathing
• cough
• chest pain
• fever

Inform your doctor or nurse immediately if you notice one or more of the following side effects, as they may be signs of an allergic reaction:

• difficulty breathing
• fever
• sudden weight gain
• water retention
• loss of consciousness
• palpitations (strong heartbeat felt in the chest)

While you are being treated with Trióxido de Arsénico 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 (inflammation 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 hemorrhage, hypoxia (low oxygen level), pericardial or pulmonary effusion, hypotension, cardiac rhythm alteration
• seizures, bone or joint pain, vascular inflammation
• increased sodium or magnesium, ketones in the blood and urine (ketoacidosis), kidney function test abnormalities, renal insufficiency
• abdominal pain
• skin redness, facial swelling, blurred vision

Unknown frequency (cannot be estimated from available data):

• pulmonary infection, sepsis
• inflammatory lung disease with chest pain and difficulty breathing, heart failure,
• dehydration, confusion
• brain disease (Wernicke encephalopathy) with various manifestations, including difficulty using arms and legs, speech disorders, and confusion.

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect not listed in this prospectus. You can alsoreport them directly through the national notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date shown on the vial label and the box.

This medication does not require special storage conditions.

After initial opening: once opened, the product must be used immediately.

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

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

Do not use this medication if you observe foreign particles or if the solution is discolored.

Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications you no longer need. This will help protect the environment.

Composition of Arsenic Trioxide Accord

• The active principle is arsenic trioxide. 1 mL of concentrate contains 1 mg of arsenic trioxide. A vial contains 10 mg of arsenic trioxide.
• The other components are sodium hydroxide, concentrated hydrochloric acid (for pH adjustment) and injection water. See Section 2: “Arsenic Trioxide Accord contains sodium”.

Appearance of the product and contents of the container

Arsenic Trioxide Accord is a concentrate for perfusion solution. Arsenic Trioxide Accord is supplied in glass vials in the form of a concentrated aqueous solution, transparent, colorless and sterile

Each box contains 1, 5 or 10 glass vials.

Only some sizes of packaging may be commercially marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6th floor,

08039 Barcelona,

Spain

Responsible for manufacturing

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

Last review date of this leaflet: August 2020

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

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This information is intended solely for doctors or healthcare professionals:

IT MUST BE FOLLOWED STRICTLY A TECHNIQUE ASPIRATION DURING THE HANDLING OF ARSENIC TRIOXIDE ACCORD SINCE IT DOES NOT HAVE PRESERVATIVES.

Dilution of Arsenic Trioxide Accord

Arsenic Trioxide Accord must be diluted before administration. Bags of plastic without PVC should be used.

The staff must be properly trained to handle and dilute arsenic trioxide and must wear suitable protective equipment.

Dilution:Insert the needle of a syringe carefully into the vial through the stopper and extract all the content. Arsenic Trioxide Accord must be diluted immediately 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 vialwill be disposed of in the appropriate manner. Do not store any unused portion for subsequent administration.

Use of Arsenic Trioxide Accord

Arsenic Trioxide Accord is for single use. It must not be mixed or administered concomitantly by the same intravenous route with other medications.

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

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

After diluting 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 must be used immediately. If not used immediately, the storage conditions and times before use are the responsibility of the user and are normally not greater than 24 hours at 2-8°C, unless the dilution has been carried out in validated and controlled aseptic conditions.

Procedure for correct disposal

The disposal of unused medication and all materials that have been in contact with it will be carried out in accordance with local regulations.