Arsenic trioxide Accord

Package leaflet: Information for the patient

Trioxido di arsenico Accord 1 mg/mL concentrate for solution for infusion

arsenic trioxide
Read this leaflet carefully before you are given this medicine
because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet

1. What Trioxido di arsenico Accord is and what it is used for
2. What you need to know before you are given Trioxido di arsenico Accord
3. How Trioxido di arsenico Accord is given
4. Possible side effects
5. How to store Trioxido di arsenico Accord
6. Contents of the pack and other information

1. What Triossido di arsenico Accord is and what it is used for

Triossido di arsenico Accord is an antitumour medicinal product used in adult patients with newly diagnosed low/intermediate-risk acute promyelocytic leukaemia (APL), and in adult patients whose disease has not responded to other therapies. APL is a distinct variant of myeloid leukaemia, a disease characterised by abnormalities in blood white cells and abnormalities in bleeding and bruising.

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

Trioxide of Arsenic Accord must be administered under the supervision of a physician experienced in
the treatment of acute leukemias.
Do not take Trioxide of Arsenic Accord
if you are allergic to arsenic trioxide or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
You should speak with your doctor or nurse before being administered Trioxide of Arsenic Accord if:

• you have impaired renal function.
• you have liver problems.

Your doctor will take the following precautions:

• Before administering the first dose of Trioxide of Arsenic Accord, blood tests will be performed to check the levels of potassium, magnesium, calcium, and creatinine in your blood.
• An electrocardiogram (ECG) must be performed before the first dose is administered.
• During treatment with Trioxide of Arsenic Accord, blood tests (for potassium, calcium, magnesium, and liver function) must be repeated regularly.
• Additionally, an electrocardiogram will be performed twice a week.
• If you are at risk of a certain type of heart rhythm disorder (e.g., torsades de pointes or QTc prolongation), your heart will be continuously monitored.
• Your doctor may monitor your health status during and after treatment, as arsenic trioxide, the active substance in Trioxide of Arsenic Accord, may cause other tumors. You must report any new or unusual symptoms or conditions whenever you see your doctor.
• If you are at risk of vitamin B1 deficiency, checks of your cognitive and motor functions will be performed.

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

Other medicines and Trioxide of Arsenic Accord
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those not requiring a prescription.
In particular, inform your doctor:

• if you are taking any medicine that may cause changes in heart rhythm. These include:
  • Certain types of antiarrhythmics (medicines used to correct irregular heartbeats, e.g., quinidine, amiodarone, sotalol, dofetilide)
  • Medicines for the treatment of psychosis (loss of contact with reality, e.g., thioridazine)
  • Medicines for depression (e.g., amitriptiline)
  • Certain types of medicines for bacterial infections (e.g., erythromycin and sparfloxacin)
  • Certain antihistamines used for allergies such as hay fever (e.g., terfenadine and astemizole)
  • Any medicine that causes a decrease in magnesium or potassium in the blood (e.g., amphotericin B)
  • Cisapride (a medicine used for certain stomach problems). The effect of these medicines on your heart rhythm may be worsened by Trioxide of Arsenic Accord. Make sure you have informed your doctor about all medicines you are taking.
• if you are taking or have recently taken any medicine that may affect the liver. If in doubt, show your doctor the container or packaging.

Trioxide of Arsenic Accord with food and drink
There are no restrictions on food or drink that you may consume while receiving Trioxide of Arsenic Accord.

Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine.
Trioxide of Arsenic Accord may harm the fetus if used in pregnant women.
If you are of childbearing potential, you must use an effective method of contraception during treatment with Trioxide of Arsenic Accord and for 6 months after the end of treatment.
If you are pregnant or become pregnant during treatment with Trioxide of Arsenic Accord, consult your doctor.
Men must use effective contraception and must be advised not to father a child during treatment with Trioxide of Arsenic Accord and for 3 months after the end of treatment.

Breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Arsenic contained in Trioxide of Arsenic Accord passes into breast milk.
Because Trioxide of Arsenic Accord may harm breastfed infants, do not breastfeed during treatment and for up to two weeks after the last dose of Trioxide of Arsenic Accord.

Driving and using machines
Trioxide of Arsenic Accord does not affect or has negligible effect on the ability to drive or operate machinery.
However, if you experience any discomfort or adverse effects after an injection of Trioxide of Arsenic Accord, wait until symptoms have resolved before driving or operating machinery.

Trioxide of Arsenic Accord contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially ‘sodium-free’.

3. How Triossido di arsenico Accord is administered

Duration and frequency of treatment
Patients with newly diagnosed acute promyelocytic leukaemia
Your doctor will give you Triossido di arsenico Accord once daily as an infusion. During the first treatment cycle, you may be treated every day for up to 60 days, or until your doctor determines that your disease has improved.
If your disease responds to Triossido di arsenico Accord, you will receive an additional 4 treatment cycles. Each cycle consists of 20 doses, administered 5 days per week (followed by 2 days off) for 4 weeks, followed by a 4-week break. Your doctor will decide exactly how long you should continue treatment with Triossido di arsenico Accord.

Patients with acute promyelocytic leukaemia whose disease has not responded to other treatments
Your doctor will give you Triossido di arsenico Accord once daily as an infusion. During the first treatment cycle, you may be treated every day for up to 50 days, or until your doctor determines that your disease has improved.
If your disease responds to Triossido di arsenico Accord, you will receive a second treatment cycle consisting of 25 doses, administered 5 days per week (followed by 2 days off) for 5 weeks. Your doctor will decide exactly how long you should continue treatment with Triossido di arsenico Accord.

Method and route of administration
Triossido di arsenico Accord must be diluted with a glucose-containing solution or with a sodium chloride-containing solution.
Triossido di arsenico Accord is usually administered by a doctor or nurse. It is given by intravenous infusion over 1–2 hours. However, the infusion may take longer if side effects such as flushing or dizziness occur.
Triossido di arsenico Accord must not be mixed with other medicines nor infused through the same tubing used for other medicines.

If you are given more Triossido di arsenico Accord than you should
You may experience seizures, muscle weakness, and confusion. In this case, treatment with Triossido di arsenico Accord must be stopped immediately, and your doctor will treat the arsenic overdose.

If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Immediately tell your doctor or nurse if you notice the following side effects, which may be signs of a serious condition called "differentiation syndrome", which can be fatal:

• difficulty breathing
• cough
• chest pain
• fever

Immediately tell your doctor or nurse if you notice one or more of the following side effects, which may be signs of an allergic reaction:

• difficulty breathing
• fever
• sudden weight gain
• fluid retention
• fainting
• palpitations (strong heartbeats that you can feel in your chest)

During treatment with Triossido di arsenico Accord, you may experience some of the following reactions:
Very common (may affect more than 1 in 10 people)

• fatigue (tiredness), pain, fever, headache
• nausea, vomiting, diarrhoea
• dizziness, muscle pain, numbness or tingling
• skin rash or itching, increased blood sugar, oedema (swelling due to excess fluid)
• shortness of breath, fast heartbeat, abnormal ECG trace
• decreased potassium or magnesium in the blood, abnormal liver function tests including increased levels of bilirubin or gamma-glutamyl transferase in the blood

Common (may affect up to 1 in 10 people)

• reduction in blood cells (platelets, red and/or white blood cells), increase in white blood cells
• chills, weight gain
• fever due to infection and low levels of white blood cells, herpes zoster infection
• chest pain, lung bleeding, hypoxia (low oxygen levels), fluid accumulation around the heart or lungs, low blood pressure, abnormal heart rhythm
• convulsion, joint or bone pain, inflammation of blood vessels
• increased sodium or magnesium, ketones in blood and urine (ketoacidosis), abnormal kidney function tests, kidney failure
• stomach (abdominal) pain
• skin redness, facial swelling, blurred vision

Not known (frequency cannot be estimated from the available data)

• lung infections, blood infections
• lung inflammation causing chest pain and breathlessness, 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 effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system detailed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Triossido di arsenico Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the carton.
This medicine does not require any special storage conditions.
After opening: use this medicine immediately after opening.
Period of validity after dilution.
Chemical and physical in-use stability has been demonstrated for 168 hours at 25 °C and at 2 °C - 8 °C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of in-use storage prior to use are the responsibility of the user and normally should not exceed 24 hours at 2 °C - 8 °C, unless dilution has been carried out under controlled and validated aseptic conditions.
Do not use this medicine if you notice the presence of foreign particles or if the solution appears discoloured.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Triossido di arsenico Accord contains

• The active substance is arsenic trioxide. Each mL of concentrate contains 1 mg of arsenic trioxide. Each 10 mL vial contains 10 mg of arsenic trioxide.
• The other components are sodium hydroxide, concentrated hydrochloric acid and water for injections (to adjust pH). See section 2 “Triossido di arsenico Accord contains sodium”.

Description of the appearance of Triossido di arsenico Accord and package contents

• Triossido di arsenico Accord is a concentrate for solution for infusion (sterile concentrate). Triossido di arsenico Accord is supplied in glass vials as a clear, colourless aqueous concentrated solution. Each carton contains 1, 5 or 10 single-use glass vials.

Not all pack sizes may be marketed.
Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center, Moll de Barcelona s/n,
Edifici Est, 6th floor,
08039 Barcelona,
Spain
Manufacturer
Accord Healthcare Polska Sp.z o.o.,
ul. Lutomierska 50,
95-200 Pabianice,
Poland
For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
AT / BE / BG / CY / CZ / DE / DK / EE / FI / FR / HR / HU / IE / IS / IT / LT / LV / LX / MT / NL
/ NO / PT / PL / RO / SE / SI / SK / ES
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64
EL
Win Medica Pharmaceutical S.A.
Tel: +30 210 7488 821
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu .

The following information is intended exclusively for physicians or healthcare professionals:
A STRICT ASEPTIC TECHNIQUE MUST BE FOLLOWED FOR ALL
PROCEDURES INVOLVING THE HANDLING OF TRIOSSIDO DI ARSENICO ACCORD,
DUE TO THE ABSENCE OF A PRESERVATIVE IN THE PRODUCT.
Dilution of Triossido di arsenico Accord
Triossido di arsenico Accord must be diluted before administration. Use non-PVC plastic bags.
Personnel must be trained in the handling and dilution of arsenic trioxide and must wear appropriate protective clothing.
Dilution: Carefully insert the needle of a syringe through the rubber stopper of the vial and withdraw the entire contents.
Immediately dilute Triossido di arsenico Accord with 100–250 mL of glucose 50 mg/mL (5%) solution for injection or sodium chloride 9 mg/mL (0.9%) solution for injection.
Any unused portions from each vial must be properly disposed of. Do not store unused portions for subsequent administration.
Use of Triossido di arsenico Accord
Triossido di arsenico Accord is for single use only. It must not be mixed with other medicinal products nor administered simultaneously with other drugs through the same intravenous line.
Triossido di arsenico Accord must be administered intravenously over 1–2 hours. The infusion duration may be extended up to a maximum of 4 hours if vasomotor reactions occur. A central venous catheter is not required.
The diluted solution must be clear and colourless. All parenteral solutions should be inspected visually for particulate matter and discolouration prior to administration. Do not use the preparation if it contains foreign particulate matter.
After dilution in intravenous solutions, Triossido di arsenico Accord remains chemically and physically stable for 168 hours at 25°C and under refrigerated conditions (2–8°C). From a microbiological standpoint, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2–8°C, unless dilution has been carried out under controlled and validated aseptic conditions.
Procedure for proper disposal
Unused medicinal product, items that have come into contact with the product, and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.