TRISENOX 2 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

TRISENOX 2mg/ml concentrate for solution for infusion

arsenic trioxide

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

Contents of the pack

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

1. What TRISENOX is and what it is used for

TRISENOX is used in adult patients with low to intermediate risk acute promyelocytic leukaemia (APL) who have just been diagnosed, and in adult patients whose disease has not responded to other treatments. APL is a unique type of myeloid leukaemia, a disease that produces abnormal white blood cells, bleeding, and bruising.

2. What you need to know before you are given TRISENOX

TRISENOX should be given under the supervision of a doctor who is experienced in the treatment of acute leukaemias.

You should not be given TRISENOX

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 TRISENOX, if

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

Your doctor will take the following precautions:

• Tests will be done to check the levels of potassium, magnesium, calcium, and creatinine in your blood before the first dose of TRISENOX.
• You will have an electrocardiogram (ECG) before the first dose.
• Blood tests (potassium, calcium, liver function) will be repeated while you are being treated with TRISENOX.
• You will also 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 prolonged 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.
• Monitoring of cognitive and motor functions if you are at risk of vitamin B1 deficiency.

Children and adolescents

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

Other medicines and TRISENOX

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 change your 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 hay fever, called antihistamines (e.g. terfenadine and astemizole)
• any medicine that may lower the levels of magnesium or potassium in your blood (e.g. amphotericin B)
• cisapride (a medicine used to relieve certain stomach problems).

The effect of these medicines on your heart rhythm may be worsened by TRISENOX. You must make sure that you tell your doctor about all the medicines you are taking.

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

Using TRISENOX with food and drink

There are no restrictions on food or drink while you are being treated with TRISENOX.

Pregnancy

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

TRISENOX may harm your unborn baby if you are given it while you are pregnant.

If you can become pregnant, you must use effective contraception during treatment with TRISENOX and for 6 months after the end of treatment.

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

Men must use effective contraception and be advised not to father a child during treatment with TRISENOX and for 3 months after the end of treatment.

Breast-feeding

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

Arsenic from TRISENOX passes into breast milk.

As TRISENOX may harm your baby, you must not breast-feed while you are being treated with TRISENOX and for 2 weeks after the last dose of TRISENOX.

Driving and using machines

TRISENOX is unlikely to affect your ability to drive or use machines.

If you feel unwell or experience side effects after an injection of TRISENOX, do not drive or use machines until the symptoms have gone away.

TRISENOX contains sodium

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

3. How TRISENOX is given

Duration and frequency of treatment

Patient with newly diagnosed acute promyelocytic leukaemia

Your doctor will give you TRISENOX once a day by infusion. In the first cycle of treatment, you may receive treatment every day for up to 60 days, or until your doctor decides that your disease has improved. If your disease responds to TRISENOX, you will receive 4 additional cycles of treatment. Each cycle consists of 20 doses, given 5 days a 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 TRISENOX.

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

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

Form and route of administration

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

TRISENOX is usually given by a doctor or nurse. It is given through a drip (infusion) into a vein over 1-2 hours, but the infusion may take longer if you experience side effects such as flushing and dizziness.

TRISENOX must not be mixed or injected with other medicines through the same tube.

If your doctor or nurse gives you more TRISENOX than you should have

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

If you have any further questions on 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 may be signs of a serious condition called "differentiation syndrome", which can be life-threatening:

• difficulty breathing
• coughing
• chest pain
• fever

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

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

While you are being treated with TRISENOX, 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, diarrhoea
• dizziness, muscle pain, numbness or tingling
• skin rash or itching, high blood sugar, swelling (inflammation due to excess fluid)
• shortness of breath, palpitations, abnormal electrocardiogram
• low levels of potassium or magnesium in the blood, abnormal liver or kidney function tests, including high levels of bilirubin or gamma-glutamyltransferase in the blood

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

• low blood cell count (platelets, red blood cells, and/or white blood cells), high white blood cell count
• chills, weight gain
• fever due to infection and low white blood cell count, herpes zoster infection
• chest pain, bleeding in the lungs, low oxygen levels, fluid accumulation in the sac around the heart or in the lungs, low blood pressure, irregular heartbeat
• seizures, bone or joint pain, inflammation of blood vessels
• high levels of sodium or magnesium, presence of ketones in blood and urine (ketoacidosis), abnormal kidney function tests, kidney failure
• stomach pain (abdomen)
• redness of the skin, facial swelling, blurred vision

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

• lung 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 symptoms, including difficulty using arms and legs, speech disorders, and confusion

Reporting of side effects

If you experience any side effects, talk to 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 TRISENOX

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 vial label and carton.

No special storage conditions are required.

After dilution, if not used immediately, the storage conditions and storage time before use are the responsibility of the user and are normally not more than 24 hours at 2-8°C, unless the dilution has been carried out under aseptic conditions.

Do not use this medicine if you notice any visible signs of deterioration or if the solution is discoloured.

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 other information

What TRISENOX contains

• The active substance is arsenic trioxide. Each millilitre of concentrate contains 2 mg of arsenic trioxide. Each 6 ml vial contains 12 mg of arsenic trioxide.
• The other ingredients are sodium hydroxide, hydrochloric acid, and water for injection. See section 2 "TRISENOX contains sodium".

Appearance and pack contents

TRISENOX is a concentrate for solution for infusion (sterile concentrate). TRISENOX is supplied in glass vials as a clear, colourless, aqueous solution. Each carton contains 10 single-use glass vials.

Marketing authorisation holder

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

Manufacturer

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

Date of last revision of this leaflet: {MM/YYYY}

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

There are also links to other web sites about rare diseases and orphan medicines.

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This information is intended only for healthcare professionals:

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

Dilution of TRISENOX

TRISENOX must be diluted before administration.

Personnel should be adequately trained to handle and dilute arsenic trioxide and should wear appropriate protective equipment.

Dilution: Carefully insert the needle of a syringe into the ampoule and withdraw all the contents.

TRISENOX should be diluted immediately afterwards 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 should be discarded in an appropriate manner. Do not store any unused portion for later administration.

Use of TRISENOX

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

TRISENOX 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 colourless. Before administration, all parenteral solutions should be inspected visually for particulate matter and discolouration. 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 should be used immediately. If not used immediately, the storage conditions and storage time before use are the responsibility of the user and are normally not more than 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 done in accordance with local regulations.