Arsenic trioxide TilloMed

Patient Information Leaflet: Information for the patient

Arsenic Trioxide Tillomed 2 mg/ml concentrate for solution for infusion

For use in adults
Generic medicine
Please read 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 questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

1. What Arsenic Trioxide Tillomed is and what it is used for
2. What you need to know before Arsenic Trioxide Tillomed is administered to you
3. How Arsenic Trioxide Tillomed is administered
4. Possible side effects
5. How to store Arsenic Trioxide Tillomed
6. Contents of the pack and other information

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

Arsenic Trioxide Tillomed is used in adult patients with newly diagnosed low/intermediate-risk acute promyelocytic leukemia (APL) and in adult patients whose disease has not responded to other therapies. APL is a distinct variant of myeloid leukemia, a disease characterized by abnormalities in blood white cells and abnormalities in bleeding and bruising.

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

Arsenic Trioxide Tillomed must be administered under the supervision of a physician experienced in the treatment of acute leukemias.

Do not take Arsenic Trioxide Tillomed if you are allergic to arsenic trioxide or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions Talk to your doctor or nurse before you are given Arsenic Trioxide Tillomed if:

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

Your doctor will take the following precautions:

• Before administering the first dose of Arsenic Trioxide Tillomed, 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 Arsenic Trioxide Tillomed, blood tests (for potassium, calcium, magnesium, and liver function) must be repeated.
• Furthermore, 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 may cause other tumors. You must report any new or unusual symptoms or conditions at every medical visit.
• If you are at risk of vitamin B1 deficiency, checks of your cognitive and motor functions will be performed.

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

Other medicines and Arsenic Trioxide Tillomed 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., amitriptyline);
  • certain types of antibiotics (e.g., erythromycin and sparfloxacin);
  • certain antihistamines used to treat allergies such as hay fever (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 for certain stomach problems).
    The effect of these medicines on your heart rhythm may be worsened by arsenic trioxide. 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 the container or packaging to your doctor.

Arsenic Trioxide Tillomed with food and drink There are no restrictions on food or drink while taking Arsenic Trioxide Tillomed.

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

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

Driving and using machines Arsenic trioxide does not affect or affects negligibly the ability to drive and use machines.
If you experience discomfort or illness after an injection of Arsenic Trioxide Tillomed, wait until symptoms have disappeared before driving or operating machinery.

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

3. How Arsenic Trioxide Tillomed is administered

Duration and frequency of treatment
Patients with newly diagnosed acute promyelocytic leukemia
Your doctor will administer Arsenic Trioxide Tillomed once daily, every day, as an infusion. During the first treatment cycle, you may be treated daily for up to 60 days, or until your doctor determines that your disease has improved. If your disease responds to Arsenic Trioxide Tillomed, you will receive up to 4 additional 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 treatment break. Your doctor will decide exactly how long you should continue treatment with Arsenic Trioxide Tillomed.

Patients with acute promyelocytic leukemia whose disease has not responded to other treatments
Your doctor will administer Arsenic Trioxide Tillomed once daily, every day, as an infusion. During the first treatment cycle, you may be treated daily for up to 50 days, or until your doctor determines that your disease has improved. If your disease responds to Arsenic Trioxide Tillomed, 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 Arsenic Trioxide Tillomed.

Method and route of administration
Arsenic Trioxide Tillomed must be diluted with a glucose-containing solution or a sodium chloride-containing solution.
Arsenic Trioxide Tillomed is generally 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.
Arsenic Trioxide Tillomed must not be mixed with other medicines, nor should it be infused through the same tubing used for other medicines.

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

If you have any questions 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 everybody gets them.
Tell your doctor or nurse immediately if you notice any of 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

Tell your doctor or nurse immediately 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 may feel in your chest)

During treatment with Arsenic Trioxide Tillomed, 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, rapid heartbeat, abnormal ECG
• decreased potassium or magnesium levels in the blood, abnormal liver function tests including increased blood levels of bilirubin or gamma-glutamyltransferase

Common (may affect up to 1 in 10 people)

• reduced number of blood cells (platelets, red and/or white blood cells), increased white blood cells
• chills, weight gain
• fever due to infection and low white blood cell count, herpes zoster infection
• chest pain, lung bleeding, hypoxia (low oxygen levels), fluid accumulation around the heart or lungs, low blood pressure, abnormal heart rhythm
• seizure, 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 determined from 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 get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Arsenic Trioxide Tillomed

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 dilution, if the medicinal product is not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at 2–8 °C, unless the 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 any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Arsenico Triossido Tillomed contains:
The active substance is arsenic trioxide. Each ml contains 2 mg of arsenic trioxide and each 6 ml contains 12 mg of arsenic trioxide.
The other components are: sodium hydroxide, hydrochloric acid and water for injections.

Description of the appearance of Arsenico Triossido Tillomed and the contents of the pack
Arsenico Triossido Tillomed 2 mg/ml concentrate for solution for infusion is a clear, colourless concentrated solution in a 6 ml volume, packed in a clear Type I glass vial with a chlorobutyl rubber stopper laminated with dark grey Teflon and a white MT flip-off seal. The filled vials are labelled and covered with a heat-shrinkable sleeve with a plastic base, and are available in packs of 1 vial and 10 vials.

Marketing Authorisation Holder and Manufacturer:
Marketing Authorisation Holder
Tillomed Italia S.r.l.
Viale Giulio Richard 1, Torre A
20143 Milano (MI), Italy

Manufacturer
Tillomed Malta Ltd.
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta

The following information is intended exclusively for physicians and healthcare professionals:
A STRICTLY ASEPTIC TECHNIQUE MUST BE OBSERVED FOR ALL PROCEDURES INVOLVING THE HANDLING OF ARSENICO TRIOSSIDO TILLOMED, DUE TO THE ABSENCE OF A PRESERVATIVE IN THE PRODUCT.

Dilution of Arsenico Triossido Tillomed
Arsenico Triossido Tillomed must be diluted before administration.
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 into the vial and withdraw the required volume. Then immediately dilute Arsenico Triossido Tillomed with 100–250 mL of 50 mg/mL (5%) glucose injection solution or 9 mg/mL (0.9%) sodium chloride injection solution.
Any unused portions from each vial must be appropriately disposed of. Do not store unused portions for subsequent administration.

Use of Arsenico Triossido Tillomed
Arsenico Triossido Tillomed is for single use only. It must not be mixed with other medicinal products nor administered simultaneously with them through the same intravenous line.
Arsenico Triossido Tillomed 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 discoloration prior to administration. Do not use the preparation if it contains foreign particulate matter.
After dilution in intravenous solutions, Arsenico Triossido Tillomed remains chemically and physically stable for 48 hours at 15–30°C and for 96 hours under refrigerated conditions (2–8°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 2–8°C, unless dilution has been carried out under controlled and validated aseptic conditions.

Procedure for proper disposal
Unused medicine, items that have come into contact with the product, and waste materials arising from this medicine must be disposed of in accordance with local regulations.