Patient Information Leaflet

TRISENOX 2mg/ml Concentrate for Solution for Infusion

arsenic trioxide

Read this leaflet carefully before you receive this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist or nurse.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section4.

1.What TRISENOX is and what it is used for

2.What you need to knowbefore you receiveTRISENOX

3.How TRISENOX is administered

4.Possible side effects

5.Storage of TRISENOX

6.Contents of the pack and additional information

TRISENOX 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.

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

Do not receive TRISENOX

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 TRISENOX is administered to you,if

• You have kidney insufficiency.
• 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 the blood before the first dose of TRISENOX.
• You will need to have an electrocardiogram or ECG before the first dose.
• Blood tests (potassium, calcium, liver function) will be repeated while you continue treatment with TRISENOX.
• In addition, you will have an electrocardiogram twice a week.
• If you are at risk of a certain type of heart rhythm anomaly (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 TRISENOX, may cause other cancers. You should report any new or unusual symptoms or circumstances to your doctor whenever you visit.
• Monitoring of cognitive function and mobility if you are at risk of vitamin B1 deficiency.

Children and adolescents

TRISENOX is not recommended for children or adolescents under 18years.

Other medications and TRISENOX

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.

Particularly, 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 TRISENOX. You should ensure that you inform your doctor about all the medications you are taking.

• 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 TRISENOX with food and drinks

There are no restrictions on food or drink while receiving TRISENOX.

Pregnancy

Consult your doctor or pharmacist before using any medication.

TRISENOX may cause damage to the fetus if administered to pregnant women.

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

If you become pregnant or become pregnant during treatment with TRISENOX, consult your doctor.

Males should use effective contraceptive methodsand should be advised not to father a childduring treatment with TRISENOXand for 3months after the end of treatment.

Lactation

Consult your doctor or pharmacist before using any medication.

Arsenic in TRISENOX passes into breast milk.

As TRISENOX may harm the infant, avoid breastfeeding while on treatment with TRISENOX and for two weeks after the last dose of TRISENOX.

Driving and operating machines

It is expected that the influence of TRISENOX on your ability to drive and operate machines will be negligible or insignificant.

If you experience discomfort or do not feel well after an injection of TRISENOX, you should wait for the symptoms to disappear before driving or operating machines.

TRISENOX contains sodium

TRISENOX contains less than 1mmol of sodium (23mg) 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 TRISENOX 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 that your condition has improved. If your condition responds to TRISENOX, you will receive 4 additional treatment cycles. Each cycle consists of 20 doses, which will be administered 5 days a week (followed by 2 days of interruption) for 4 weeks (followed by a 4-week interruption). Your doctor will decide exactly how long you should continue with TRISENOX treatment.

Patients with acute promyelocytic leukemia whose condition has not responded to other treatments

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

Form and route of administration

TRISENOX must be diluted with a solution containing glucose or a solution containing sodium chloride.

TRISENOX is usually administered by a doctor or nurse. It is administered through a drip (infusion) inserted into a vein for 1-2 hours, but the infusion may last longer if side effects such as hot flashes and dizziness occur.

TRISENOX should not be mixed or injected through the same tube with other medications.

If your doctor or nurse administers more TRISENOX than you should

You may experience seizures, muscle weakness, and confusion. If this happens, treatment with TRISENOX 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 can cause side effects, although not everyone will experience them.

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

• difficulty breathing
• coughing
• chest pain
• fever

Inform your doctor or nurse immediately if you notice one or more of the following side effects, as they could 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 TRISENOX, you may experience some of the following reactions:

Very common side effects (can 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, ECG abnormalities
• decreased potassium or magnesium in the blood, liver or kidney function abnormalities including excessive bilirubin or gamma-glutamyltransferase in the blood

Common side effects (can 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 arrhythmia
• seizures, bone or joint pain, vascular inflammation
• increased sodium or magnesium, ketosis in blood and urine (ketoacidosis), kidney function abnormalities, renal insufficiency
• abdominal pain
• skin redness, facial swelling, blurred vision

Unknown frequency (cannot be estimated from available data):

• pulmonary infection, blood infection
• chest pain and difficulty breathing due to lung inflammation, 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 also report 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 that appears on the vial label and on the box.

No special storage conditions are required.

After dilution, if it is not used immediately, storage conditions and times before use are the responsibility of the doctor, pharmacist or nurseand are normally not greater than 24 hours between 2 and8°C, 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 inthe trash. Askyour pharmacist how to dispose of the containers and medications that you no longer need. In this way, you will help protect the environment.

Composition of TRISENOX

• The active ingredient is arsenic trioxide. Each milliliter of concentrate contains 2 mg of arsenic trioxide. Each vial of 6 ml contains 12 mg of arsenic trioxide.
• The other components are sodium hydroxide, hydrochloric acid, and water for injection. See section 2 “TRISENOX contains sodium”.

Appearance of the product and contents of the pack

TRISENOX is a concentrate for solution for infusion (sterile concentrate). TRISENOX is supplied in glass vials in the form of a concentrated solution, transparent, colorless, and aqueous. Each box contains 10 single-use glass vials.

Marketing Authorization Holder

Teva B.V., Swensweg 5, 2031 GA Haarlem, Netherlands

Responsible for manufacturing

Teva Pharmaceuticals Europe B.V., Swensweg 5, 2031 GA Haarlem, Netherlands

Merckle GmbH,Graf-Arco-Str-3, 89079 Ulm, Germany

S.C. Sindan-Pharma S.R.L.,B-dul Ion Mihalache nr 11, sector 1, Cod 011171, Bucharest, Romania

Last review date of this leaflet: {MM/AAAA}

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

There are also links to other websites on rare diseases and orphan medicines.

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This information is intended solely for medical professionals or healthcare professionals:

IT MUST BE FOLLOWED STRICTLY A TECHNIQUE ASÉPTICA DURING THE HANDLING OF TRISENOX SINCE IT DOES NOT HAVE PRESERVATIVES.

Dilution of TRISENOX

TRISENOX must be diluted before administration.

The personnel 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 and extract all the contents.

TRISENOX must be diluted immediately with 100 to 250ml of injectable glucose solution 50mg/ml (5%) or injectable sodium chloride 9mg/ml (0.9%).

Unused portions of each vialmust be disposed of properly. Do not store any unused portion for subsequent administration.

Use of TRISENOX

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

TRISENOX will be administered intravenously over 1-2 hours, but the duration of the infusion may be extended 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 dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at 15-30°C and for 72 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 come into contact with it will be carried out in accordance with local regulations.