MELFALAN ZENTIVA 50 mg POWDER AND SOLVENT FOR INJECTION AND INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Melfalán Zentiva 50 mg powder and solvent for solution for injection and infusion EFG

Read all of this leaflet carefully before you start using 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 or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the pack

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

1. What Melfalán Zentiva is and what it is used for

Melfalán Zentiva contains the active substance melphalan. Melphalan belongs to a group of medicines called cytotoxics (also known as antineoplastic agents). Melphalan is used to treat cancer. It works by reducing the number of cancer cells produced by the body.

Melfalán Zentiva is used for:

• Multiple myeloma - a type of cancer that develops in the bone marrow cells called plasma cells. Plasma cells help fight infections and diseases by producing antibodies.
• Advanced ovarian carcinoma.
• Childhood neuroblastoma - cancer of the nervous system.
• Malignant melanoma - skin cancer.
• Soft tissue sarcoma - cancer of the muscles, fat, fibrous tissue, blood vessels, or other supporting tissue of the body.

You should consult a doctor if you want 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 Melfalán Zentiva

You will not be given Melfalán Zentiva if

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

If you are not sure, consult your doctor or nurse before administration of melphalan.

Warnings and precautions

Before treatment with Melfalán, tell your doctor if any of the following apply to you:

• 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) can cause an infection if given while being treated with melphalan,
• you have a blood clot in your leg (thrombosis), lung (pulmonary embolism), or any other part of your body, or have ever had one,
• you have a condition that increases the chances of you forming blood clots in your arteries,
• 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.

Melphalan may increase the risk of developing another type of cancer (e.g., secondary solid tumors) in a small number of patients, particularly when used in combination with lenalidomide, thalidomide, and prednisone. Your doctor will carefully evaluate the risks and benefits when prescribing melphalan.

Men who receive melphalan should not father children during treatment or for up to 3 months after treatment.

If you have any doubts about whether what you have read affects you, consult your doctor or pharmacist before taking melphalan.

Other medicines and Melfalán Zentiva

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

In particular, tell your doctor if you are using medicines such as:

• other cytostatic agents (antineoplastic agents)
• nalidixic acid (an antibiotic used to treat urinary tract infections)
• cyclosporin (used to prevent rejection after a transplant, to treat certain skin diseases such as psoriasis and eczema, or to treat rheumatoid arthritis)
• vaccines that contain live microorganisms (see Warnings and precautions)
• in children, busulfan (used to treat a certain type of cancer)

Pregnancy, breast-feeding, and fertility

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or plan to become pregnant, consult your doctor before you are given this medicine.

Pregnancy

During pregnancy, treatment with melphalan is not recommended because it may harm the fetus. Do not take melphalan if you are planning to have a child. This applies to both men and women. Effective contraceptive measures should be used to avoid pregnancy while you or your partner are receiving this injectable medicine.

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

Breast-feeding

It is not known if melphalan is excreted in breast milk. Do not breast-feed while receiving melphalan.

Fertility

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

Contraception for men and women

Women of childbearing age must use effective contraceptive measures during treatment with melphalan and for up to 6 months after finishing treatment.

It is recommended that men who receive melphalan do not father children during treatment and for up to 3 months after treatment. Talk to your doctor if you want to use effective and reliable contraceptive methods.

Driving and using machines

The effects of this medicine on the ability to drive or use machines have not been studied. It is not expected that this medicine will affect the ability to drive or use machines.

Melfalán Zentiva contains sodium

This medicine contains 53.5 mg of sodium per vial (a component of table salt/cooking salt) in each vial. This is equivalent to 2.7% of the maximum recommended daily intake of sodium for an adult.

Melfalán Zentiva contains ethanol

This medicine contains 5% ethanol (alcohol), which corresponds to an amount of 0.4 g per vial, equivalent to 10 ml of beer or 4 ml of wine per vial.

This medicine is harmful to people with alcoholism.

The alcohol content should be taken into account in the case of pregnant women, children, and high-risk groups, such as patients with liver disease or epilepsy.

The amount of alcohol contained in this medicine may alter the effect of other medicines.

The amount of alcohol contained in this medicine may affect your ability to drive and use machines because it can alter your judgment and reaction ability.

Melfalán Zentiva contains propylene glycol

This medicine contains 6.2 g of propylene glycol in each vial.

Propylene glycol in this medicine may produce effects similar to those produced by drinking alcohol and increase the likelihood of these adverse effects.

Do not use this medicine in children under 5 years of age.

Use this medicine only if it is recommended by a doctor.

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

3. How Melfalán Zentiva is administered

Melfalán will only be administered to you by doctors or nurses with experience in chemotherapy.

Melfalán is a cytotoxic agent that should only be used under the direction of doctors with experience in the administration of such agents.

Method of administration

Melfalán can be administered:

• as an infusion (drip) into one of your veins.
• into an artery, administered to a specific part of the body (perfusion).

How much melphalan is administered

Your doctor will decide the dose of melphalan that you should be given. The treatment dose will depend on:

• your weight or body surface area (a specific measure that takes into account your weight and size),
• other medicines you are taking,
• the disease being treated,
• your age,
• if you have kidney problems.

Periodically, your doctor will tell you to have a blood test to check your blood count and change the dose if necessary.

Risk of blood clots(thromboembolic episodes)

Your doctor will determine if you should receive preventive treatment for blood clots in the veins. This applies during the first 5 months of treatment or if you have an increased risk of developing blood clots in the veins.

Use in children

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

Use in elderly patients

There are no specific dose adjustments for this age group.

Use in patients with renal impairment

If you have kidney problems, your doctor will usually prescribe a lower dose than for other adults.

If you are given too much Melfalán Zentiva

Your doctor will administer the dose of melphalan, so it is unlikely that you will receive too much. If you think you have been given too much or have missed a dose, tell your doctor or nurse.

If you miss a dose of Melfalán Zentiva

Your doctor will administer melphalan, so it is unlikely that you will miss a dose of this medicine. If you think you have missed a dose, skip that dose and you will be given the next dose at the next scheduled time. Do not use a double dose to make up for a missed dose.

If you stop treatment with Melfalán Zentiva

If you think you should stop using this medicine, consult your doctor first.

If you have any further questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

Serious side effects

Talk to your doctor or go to the hospital immediately if you notice any of the following effects:

• allergic reaction, the signs may include:
• • a rash, lumps, or hives on the skin
  • swollen face, eyelids, or lips
  • sudden onset of "wheezing" and tightness in the chest
  • fainting (due to cardiac arrest)
• any sign of fever or infection (sore throat, mouth ulcers, or urinary problems).
• treatment with melphalan may 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 with a normal temperature).
• if your muscles are painful, stiff, or weak and your urine appears darker than usual or has a brown or reddish color - when melphalan is administered directly into the arm or leg.
• if you experience any of the signs/symptoms that may be related to a blood clot (thromboembolic event), such as difficulty breathing, chest pain, swelling of arms or legs, especially if you are being treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone.
• if melphalan is injected directly into the arm or leg, it is possible that some of the medicine may leak into the surrounding tissues and 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 may cause necrosis of the surrounding skin, ulcers, and damage to deeper tissue.

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

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

• a decrease in the number of white blood cells and platelets
• nausea, vomiting, and diarrhea - with high doses of melphalan
• mouth ulcers (with high doses of melphalan)
• hair loss (with high doses of melphalan)
• a feeling of tingling or warmth where melphalan has been injected
• muscle problems such as atrophy and pain - when melphalan is administered directly into the arm or leg

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

• hair loss with usual doses of melphalan.
• high levels of a chemical called urea in the blood in people with kidney problems who are being treated for myeloma.
• a muscle problem that can cause pain, pressure, tingling, burning, or numbness called compartment syndrome. This can occur when melphalan is administered directly into the arm or leg.
• inflammation of the soft tissue that lines the stomach (gastrointestinal mucosa).

Uncommon side effects (may affect up to 1 in 100 people):

• acute kidney failure.

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

• a disease in which you have a low number of red blood cells because they are destroyed prematurely - this can make you feel very tired, short of breath, and dizzy, and may cause headaches or yellowing of the skin and eyes.
• lung problems that can cause you to 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 and eyes (jaundice).
• mouth ulcers with normal doses of melphalan.
• skin rashes or itching.

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

• leukemia (blood cancer).
• in women: disappearance of periods (amenorrhea).
• in men: absence of sperm in the semen (azoospermia).
• death of muscle tissue (muscle necrosis).
• rupture of muscle fibers (rhabdomyolysis).
• formation of a blood clot (thrombosis) in a deep vein, mainly in the legs (deep vein thrombosis) and blockage of a pulmonary artery (pulmonary embolism).

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.

It is possible that the use of melphalan may increase the risk of developing another type of cancer called secondary acute leukemia (blood cancer) in the future. Secondary acute leukemia 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 will show 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 melphalan, but only your doctor can tell you if that is the case.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report side effects directly through 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. Storage of Melfalán Zentiva

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 carton after EXP. The expiry date is the last day of the month shown.

This medicine does not require any special storage temperature.

Keep the vial in the outer packaging to protect it from light.

Melfalán must be prepared by a healthcare professional. Once the solution is reconstituted, it should be used immediately. The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

6. Container Content and Additional Information

Composition of Melfalán Zentiva

The active principle is melfalán. Each vial contains 50 mg of melfalán.

The other components (excipients) are:

Vial with powder: povidone K12 and diluted hydrochloric acid.

Vial with solvent: contains water for injectable preparations, sodium citrate dihydrate, propylene glycol, and ethanol.

Melfalán is dissolved in a solvent before being administered.

Appearance of the Product and Container Content

Each container contains a vial with powder and a vial with solvent.

The vial with powder contains 50 mg of the active substance melfalán in powder form, and the vial with solvent contains 10 ml of solvent used to reconstitute (dissolve) the powder.

When the melfalán powder vial is reconstituted with the 10 ml of solvent, the resulting solution contains 5mg/ml of anhydrous melfalán.

Powder: type I transparent glass vial with a bromobutyl rubber stopper coated with omniflex 3G and an aluminum flip-off seal with an orange polypropylene cap and a matte finish. The vials may or may not have retractable sleeves.

Each container contains 1 vial with 50 mg of melfalán.

Solvent:type I transparent glass vial with a bromobutyl rubber stopper and an aluminum flip-off seal with an orange polypropylene cap and a matte finish.

Each container contains 1 vial of 10 ml.

Marketing Authorization Holder:

Zentiva, k.s.,

U kabelovny 130,

Prague 10 – Dolní Mecholupy,

102 37 Czech Republic

Manufacturer:

SGS Pharma Magyarorszag Kft.

Derkovits Gyula Utca 53,

Budapest XIX, 1193,

Hungary

or

Tillomed Malta Limited,

Malta Life Sciences Park,

LS2.01.06 Industrial Estate,

San Gwann, SGN 3000, Malta

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Zentiva Spain S.L.U.

Avenida de Europa, 19, Edificio 3, Planta 1.

28224 Pozuelo de Alarcón, Madrid

Spain

This medicinal product is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

United Kingdom (Northern Ireland): Melphalan 50 mg Powder and Solvent for Solution for Injection/Infusion

Germany: Melphalan Tillomed 50 mg Pulver und Lösungsmittel zur Herstellung einer Injektions Infusionslösung

Italy: Melfalan Tillomed

Spain: Melfalán Zentiva 50 mg powder and solvent for injectable solution and for perfusion EFG

Cyprus: Melphalan Tillomed 50 mg

Greece: Melphalan Tillomed 50 mg

Date of the last revision of this leaflet:March 2024

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

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This information is intended exclusively for healthcare professionals:

Proper procedures for handling and disposal of cytotoxic medicinal products should be followed:

1. Employees should be instructed on the reconstitution of the medicinal product.
2. Pregnant women should be excluded from handling this medicinal product.
3. Personnel should wear suitable protective clothing, including masks, safety glasses, and gloves when reconstituting the preparation.
4. Any item used for administration or cleaning, including gloves, should be disposed of in containers for contaminated material that is subjected to high-temperature incineration. Liquid waste can be eliminated with abundant water.

In case of accidental contact with the eyes with Melfalán, rinse immediately with a sodium chloride collyrium or abundant water and consult a doctor immediately. In case of skin contact, wash the affected areas immediately with soap and abundant cold water and consult a doctor immediately. The spilled solution should be cleaned immediately with a damp absorbent paper, which should then be disposed of safely. Contaminated surfaces should be washed with abundant water.

Reconstitution

Melfalán should be prepared at room temperature (approximately 25°C), reconstituting the powder with the provided solvent-diluent.

It is essential that both the powder and the provided solvent are at room temperature (approximately 25°C) before starting reconstitution.

10 ml of the solvent should be added quickly as a single quantity to the vial containing the powder, using a sterile needle and syringe. A 21-gauge or larger needle should be used to puncture the vial stopper during reconstitution. For smooth and effective penetration, the needle should be inserted perpendicularly into the stopper, neither too quickly nor abruptly, without twisting. The vial should be shaken vigorously immediately (for approximately 5 minutes) until a clear solution without visible particles is obtained. It is crucial to add the diluent quickly followed by immediate vigorous shaking for adequate dissolution.

The agitation of the formulation produces a significant amount of very small air bubbles. These bubbles may remain for 2 to 3 minutes since the resulting solution is quite viscous. This may make it difficult to assess the clarity of the solution.

Each vial should be reconstituted individually in this manner. The resulting solution contains the equivalent of 5 mg per ml of anhydrous melfalán. If the preparation steps mentioned above are not followed, incomplete dissolution of melfalán may occur.

The melfalán solution has limited stability and should be prepared immediately before use.

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

Mixing

Take 10 ml of the previously reconstituted solution with a concentration of 5 mg/ml of anhydrous melfalán in a perfusion bag containing 100 ml of 0.9% sodium chloride injectable solution. Mix this diluted solution well to obtain a nominal concentration of 0.45 mg/ml of anhydrous melfalán.

When further diluted in a perfusion solution, melfalán has reduced stability, and the degradation rate increases rapidly with increasing temperature. If melfalán is administered at a room temperature of approximately 25°C, the maximum time from preparation of the solution to the end of perfusion should not exceed 1.5 hours.

Melfalán is not compatible with perfusion solutions containing dextrose, and it is recommended to use only 0.9% sodium chloride injectable solution (9 mg/ml).

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

Elimination

Any unused solution after 1.5 hours should be discarded according to standard guidelines for handling and disposal of cytotoxic medicinal products.

Any unused medicinal product or waste material should be disposed of according to local requirements for cytotoxic medicinal products.