ALKERAN 50 mg POWDER AND SOLVENT FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Alkeran 50 mg Powder and Solvent for Solution for Infusion

melfalán

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 or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Alkeran and what is it used for

Alkeran contains a medicine called melfalán which belongs to a group of medicines called cytotoxics (also known as chemotherapy) and is used to treat certain types of cancer. It works by reducing the number of abnormal cells your body produces.

Alkeran is used for:

• Multiple myeloma– a type of cancer that develops from cells in the bone marrow called plasma cells. Plasma cells help to fight infections and diseases by producing antibodies.
• Ovarian canceradvanced

• Advanced neuroblastoma (Stage 4)– (a type of cancer that affects the nervous system) in children
• Malignant melanoma– a type of skin cancer
• Soft tissue sarcoma– cancer of muscle tissue, fat tissue, fibrous tissue, blood vessels or other supporting tissue of the body

Ask your doctor if you would like more information about these diseases.

You should consult your doctor if it gets worse or does not improve.

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

You will not be given Alkeran

• if you are allergic to melfalán or any of the other ingredients of this medicine (listed in section 6).
• if you are breast-feeding.

If you are not sure, consult your doctor or nurse before Alkeran is administered.

Warnings and precautions

Consult your doctor or nurse before you are given Alkeran:

• if you are currently receiving or have recently received radiotherapy or chemotherapy,
• if you have any kidney disease,

• if you have been vaccinated recently or are planning to be vaccinated. This is because some vaccines (such as polio, measles, mumps and rubella) could give you an infection if they are given while you are being treated with melfalan,
• if you are taking combined oral contraceptives (the pill). This is due to the increased risk of venous thromboembolism (a blood clot that forms in a vein and moves to another location) in patients with multiple myeloma.
• if you are planning to have a child. This is due to the risk of genotoxicity (damage to genetic material) and infertility (see Pregnancy, breast-feeding and fertility).

Alkeran may increase the risk of developing another type of cancer (such as secondary solid tumours) in a small number of patients, particularly when used in combination with lenalidomide, thalidomide and prednisone. Your doctor will carefully weigh the risks and benefits when prescribing Alkeran.

If you are unsure about any of the above, consult your doctor or pharmacist before taking Alkeran.

Other medicines and Alkeran

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This includes herbal medicines.

Tell your doctor or nurse in particular if you are taking any of the following medicines:

• vaccines that contain live micro-organisms (see Warnings and precautions)
• nalidixic acid (an antibiotic used to treat urinary infections)
• cyclosporin (used to prevent organ or tissue rejection after a transplant or to treat certain skin diseases such as psoriasis and eczema or to treat rheumatoid arthritis)
• in children, busulfan (another chemotherapy drug used to treat certain types of cancer)

Pregnancy, breast-feeding and fertility

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before you are given this medicine.

Alkeran is not recommended during pregnancy because it may cause permanent damage to the fetus. Do not take Alkeran if you are planning to have a child. This applies to both men and women. Reliable and effective contraceptive methods must be used to avoid pregnancy while you or your partner are receiving this injectable medicine.

Women must use reliable and effective contraceptive methods during treatment and for 6 months after finishing treatment.

Men must use reliable and effective contraceptive methods during treatment and for 3 months after finishing treatment.

If you are already pregnant, it is important that you consult your doctor before you are given Alkeran. Your doctor will consider the risks and benefits of taking Alkeran for you and your baby.

Do not take Alkeran if you are breast-feeding. Ask your doctor for advice.

Fertility

Melfalán may affect the ovaries and sperm, which can cause infertility (inability to conceive a child). In women, menstruation may stop (amenorrhoea) and in men, a complete lack of sperm (azoospermia) may occur. Due to the possibility of loss of sperm as a result of treatment with Melfalán, men are advised to consult about sperm preservation before treatment.

Driving and using machines

The effects of this medicine on the ability to drive and use machines have not been studied in patients taking this medicine.

Alkeran contains sodium

This medicine contains 53.24 mg of sodium (main component of cooking/table salt) in each vial. This is equivalent to 2.6% of the maximum recommended daily intake of sodium for an adult.

Alkeran contains ethanol

This medicine contains 416 mg of alcohol (ethanol) in each vial, which is equivalent to 41.6 mg/ml (4% p/v). The amount in each vial of this medicine is equivalent to less than 11 ml of beer or 5 ml of wine.

The small amount of alcohol in this medicine does not produce any noticeable effect.

Alkeran contains propylene glycol

This medicine contains 6048 mg of propylene glycol in each vial, equivalent to 604.8 mg/ml.

If the child is under 5 years of age, consult your doctor or pharmacist, especially if they have been given other medicines that contain propylene glycol or alcohol.

If you are pregnant or breast-feeding, do not take this medicine unless your doctor recommends it. Your doctor may perform additional checks while you are taking this medicine.

If you have liver or kidney problems, do not take this medicine unless your doctor recommends it. Your doctor may perform additional checks while you are taking this medicine.

3. How Alkeran is given

Only a specialist doctor with experience in treating cancer can prescribe you Alkeran.

Alkeran is a cytotoxic agent that should only be used under the direction of doctors experienced in the administration of such agents.

Alkeran can be given:

• as an infusion into one of your veins
• as a perfusion into a particular area of your body through an artery.

Your doctor will decide the amount of Alkeran you should be given. The amount of Alkeran depends on:

• your body weight or body surface area (a specific measure that takes into account your weight and height)
• other medicines you are taking
• your disease
• your age
• whether or not you have kidney problems.

When you are given Alkeran, your doctor will regularly perform blood tests. This is to check the number of blood cells. Your doctor may sometimes change the dose as a result of these tests.

Thromboembolic events

There may be an increased risk of deep vein thrombosis (formation of a blood clot called a thrombus within a deep vein, mainly in the legs) and pulmonary embolism (a blockage of the main artery of the lung or its branches by a blood clot that breaks loose and travels to the lung) when melfalán is used in combination with other medicines that may affect the functioning of the immune system (such as lenalidomide/thalidomide) and others that may increase the benefits of treatment with melfalán (such as prednisone/dexamethasone).

Your doctor will determine what measures should be taken after a careful assessment of your underlying risk factors (such as smoking, high blood pressure, high lipid levels in the blood, history of thrombosis).

If you develop any signs or symptoms of thromboembolism (such as difficulty breathing, chest pain, swelling of arms or legs), consult your doctor immediately. If you experience a thromboembolic event, your doctor may decide to discontinue your treatment and start standard anticoagulation therapy. Your doctor will decide whether you should start taking melfalán again in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone once the thromboembolic events have been treated.

Neutropenia and thrombocytopenia

An increased number of blood toxicities, such as neutropenia (decrease in the number of white blood cells, which can increase the risk of infection) and thrombocytopenia (low number of platelets, which can cause bleeding and bruising) have been seen when melfalán is used in combination with other medicines that may affect the functioning of the immune system (such as lenalidomide/thalidomide) and others that may increase the benefits of treatment with melfalán (such as prednisone/dexamethasone).

Use in children

Alkeran is rarely indicated in children. There are no dosage guidelines available for children.

If you are given too much Alkeran

Your doctor will give you Alkeran so it is very unlikely that you will be given too much. If you think you have been given too much or have missed a dose, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Consult your specialist doctor or go to hospital immediately if you notice any of the following:

• allergic reaction, the signs may include:

• a rash, lumps or hives on the skin
• face, eyelids or lips swollen
• sudden onset of “wheezing” and tightness of the chest
• fainting (due to cardiac arrest)

• any sign of high temperature or infection (sore throat, mouth ulcers or urinary problems).
• Treatment with Alkeran can cause a decrease in white blood cells. White blood cells fight infections and when there are too few, an infection can occur.

• any unexpected bruising or bleeding or feeling extremely tired, dizzy or short of breath, as this could mean that you are producing too few blood cells of a certain type.
• if you suddenly do not feel well (even if you have a normal temperature).
• if your muscles are painful, stiff or weak and your urine looks darker than usual or has a brown or reddish colour – when Alkeran is given directly into your arm or leg.
• If Alkeran leaks into the tissues around the injection site, it can damage that tissue. The symptoms of this include mild discomfort of the area, slight redness of the skin or mild rash. In rare cases, it can cause necrosis of the surrounding skin, ulcers and damage to deeper tissue.
• If you experience any signs/symptoms that may be related to a thromboembolic event (such as difficulty breathing, chest pain, swelling of arms or legs) especially if you are being treated with Alkeran in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone.

Consult your doctor if you have any of the following side effects that may also occur with this medicine:

Very common (may affect more than 1 in 10 people)

• a decrease in the number of white blood cells and platelets
• nausea, vomiting and diarrhoea – with high doses of Alkeran
• mouth ulcers – with high doses of Alkeran
• hair loss – with high doses of Alkeran
• a feeling of tingling or warmth where Alkeran has been injected
• muscle problems such as wasting and pain – when Alkeran is given directly into your arm or leg.

Common (may affect up to 1 in 10 people)

• hair loss – with normal doses of Alkeran
• high levels in the blood of a chemical called urea – in people with kidney problems who are being treated for myeloma.
• a muscle problem that can cause pain, stiffness, tingling, burning or numbness – called compartment syndrome. This can happen when Alkeran is given directly into your arm or leg.

Rare (may affect up to 1 in 1,000 people)

• a disease in which you have a low number of red blood cells, as they are destroyed prematurely – this can make you feel very tired, short of breath and dizzy and can cause headaches or yellowing of the skin or eyes
• lung problems that can make you cough or wheeze and make it difficult to breathe
• liver problems that can show up in your blood tests or cause yellowing of the skin or eyes (jaundice)
• mouth ulcers – with normal doses of Alkeran
• skin rashes or itching of the skin.

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

• leukaemia – cancer of the blood
• in women: disappearance of periods (amenorrhoea)
• in men: absence of sperm in the semen (azoospermia)
• death of muscle tissue (muscle necrosis)
• breakdown of muscle fibres (rhabdomyolysis)
• deep vein thrombosis and pulmonary embolism
• acute kidney injury or kidney failure (significant deterioration of kidney function) that occurs over a short period of time

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

The use of Alkeran may increase the risk of developing another type of cancer called secondary acute leukaemia (blood cancer) in the future. Secondary acute leukaemia causes the bone marrow (tissue in the bones that produces red and white blood cells) to produce a large number of cells that do not work properly. The symptoms of this disease include tiredness, fever, infection and bruising. This disease can also be detected by a blood test that shows if there are a large number of cells in the blood that are not working properly and very few cells that are.

Tell your doctor as soon as possible if you have any of these symptoms. You may need to stop taking Alkeran, but only your doctor can decide that.

Reporting of side effects

If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. You can also report side effects directly via the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storing Alkeran

• 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 vials and carton after ‘EXP’. The expiry date is the last day of the month shown.
• Do not store above 30°C. Do not refrigerate. Keep the vials in the outer packaging to protect them from light.
• The solution of Alkeran will be prepared for use by a healthcare professional. Once prepared, it must be used immediately and must not be stored or refrigerated.

6. Container Content and Additional Information

Composition of Alkeran

• The active principle is melphalan. Each vial of Alkeran contains 50 mg of melphalan.
• The other components are povidone K12 and hydrochloric acid. Alkeran is dissolved in 10 ml of solvent before being injected. The solvent contains water for injectable preparations, sodium citrate, propylene glycol, and ethanol.

This medication contains small amounts of ethanol; less than 100 mg per dose.

It also contains 53.24 mg of sodium per vial of reconstituted product, which should be taken into account by patients on a low-sodium diet.

Appearance of the Product and Container Content

Each container contains a vial of Alkeran powder and a vial of solvent. The powder vial contains 50 mg of the active substance melphalan in powder form, and the solvent vial contains 10 ml of a solvent in which the powder is reconstituted (dissolved). When a vial of Alkeran powder is reconstituted with 10 ml of solvent, the resulting solution contains 5 mg/ml of anhydrous melphalan.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Aspen Pharma Trading Limited

3016 Lake Drive

Citywest Business Campus

Dublin 24, Ireland

Tel: +34 952 010 137

Manufacturer:

Cenexi - Laboratories Thissen S.A.

Rue de la Papyree 2-4-6,

Braine-L'Alleud, 1420,

Belgium

Date of Last Revision of this Leaflet: January 2025

Detailed information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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Information for Healthcare Professionals

For additional information, please consult the Product Technical Sheet (FT)

Instructions for Use and Handling

Safe Handling of Alkeran:

Alkeran should be prepared for administration by or under the direct supervision of a pharmacist familiar with its properties and safe handling requirements.

Consult local guidelines on cytotoxics before starting.

Alkeran should be prepared for use in the aseptic unit of a pharmacy equipped with a suitable vertical laminar flow cabinet. If such a room does not exist, a specially designated room in the plant or clinic can be used.

Personnel preparing or handling Alkeran should wear the following protective measures

• Disposable surgical latex or polyvinyl gloves of suitable quality (rubber gloves are not suitable);
• Surgical mask of suitable quality;
• Protective glasses or other glasses that should be meticulously washed with water after use;
• Disposable apron.
• In an aseptic room, other suitable clothing will be required.

Any spill should be treated immediately (by personnel wearing suitable protective clothing), cleaning it with disposable paper towels that will be disposed of in a high-risk waste bag after use, which will be disposed of in accordance with relevant local legislation. Contaminated surfaces should be washed with copious amounts of water.

If the Alkeran solution comes into contact with the skin, wash immediately and thoroughly with soap and plenty of cold water.

In such circumstances, it may be prudent to seek medical advice.

In case of eye contact, immediate irrigation should be performed with sodium chloride washing solution and medical attention should be sought without delay.

If sodium chloride solution is not available, large amounts of water can be used.

Personnel who are pregnant or trying to conceive should not handle Alkeran.

Elimination:

The Alkeran solution should be disposed of in accordance with relevant local legislation. In the absence of such guidelines, the solution should be disposed of in an appropriate manner for toxic chemicals, for example, by high-temperature incineration or deep burial.

The elimination of sharp objects, such as needles, syringes, administration equipment, and ampoules, should be carried out in rigid containers labeled with a hazardous material warning seal. Personnel involved in the elimination of these wastes should be aware of the precautions to be taken and the material should be destroyed by incineration if appropriate.

All waste disposal should be carried out in accordance with local regulatory requirements.

Preparation of the Alkeran Solution:

(See also above, Safe Handling of Alkeran).

Alkeran should be prepared, AT ROOM TEMPERATURE, by reconstituting the lyophilized powder with the provided solvent.

If the solvent is used at a cold temperature, the lyophilized powder may not reconstitute properly and undissolved particles may be observed.

10 ml of this vehicle should be added quickly, as a single amount, to the vial containing the lyophilized powder, and immediately shaken vigorously (for at least 50 seconds) until a clear, colorless solution without visible particles is obtained. Each vial should be reconstituted individually in this way. Slow addition of the solvent and delayed shaking may lead to the formation of insoluble particles. It should also be noted that the shaking process can create a considerable amount of small air bubbles. These bubbles may persist and may take 2 to 3 minutes to disappear, as the resulting solution is quite viscous.

The resulting solution contains the equivalent of 5 mg/ml of anhydrous melphalan and has a pH of approximately 6.5.

The reconstituted solution should be colorless, clear, and practically free of visible particles.

The Alkeran solution has limited stability and should be prepared immediately before use. Any unused solution should be discarded after one hour (see Elimination, above).

The reconstituted solution should not be refrigerated, as this would cause precipitation.

When Alkeran is dissolved further in an infusion solution, its stability is reduced and the degradation rate increases rapidly with increasing temperature. If administration is performed at room temperature of approximately 25°C, the total time from preparation of the injectable solution to completion of the infusion should not exceed 1.5 hours.

Alkeran is not compatible with infusion solutions containing dextrose, and it is recommended to use ONLY 0.9% w/v Sodium Chloride Intravenous Infusion. (Please consult section 4.2 of the FT).

If any visible turbidity or crystallization appears in the reconstituted solution or in the diluted solution, the preparation should be discarded.

For instructions on the administration of Alkeran, please refer to the FT.