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

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

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

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you experience any adverse reactions, consult your doctor or pharmacist, even if they are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet

1. What Melphalan Zentiva is and what it is used for
2. What you need to know before being administered Melphalan Zentiva
3. How Melphalan Zentiva is administered
4. Possible side effects
5. How to store Melphalan 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 melfalan. Melfalan belongs to a group of medicines called cytotoxic agents (also known as antineoplastic agents). Melfalan 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 bone marrow cells called plasma cells. Plasma cells help fight infections and diseases by producing antibodies.
• Advanced ovarian carcinoma.
• Childhood neuroblastoma – a cancer of the nervous system.
• Malignant melanoma – a type of skin cancer.
• Soft tissue sarcoma – cancer of the muscles, fat, fibrous tissue, blood vessels, or other supportive tissues of the body.

You should consult a doctor if you would like more information about these diseases.

Consult your doctor if your condition worsens or does not improve.

2. What you need to know before you are given Melfalan Zentiva

Do not use Melfalan Zentiva if

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

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

Warnings and precautions

Before treatment with Melfalan, inform 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 recently been vaccinated or are planning to get vaccinated. This is because some vaccines (such as polio, measles, mumps, and rubella) may cause infection if administered while you are being treated with melphalan,
• if you have a blood clot in your leg (thrombosis), lung (pulmonary embolism), or any other part of your body, or have ever had one,
• if you have a condition that increases your risk of developing blood clots in the arteries,
• if you are taking combined oral contraceptives (the pill). This is due to an increased risk of venous thromboembolism (a blood clot forming in a vein and traveling 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 must carefully evaluate the risks and benefits when prescribing melphalan.

Men receiving melphalan must not father a child during treatment or for up to 3 months afterwards.

If you have any doubts about whether the above applies to you, consult your doctor or pharmacist before taking melphalan.

Other medicines and Melfalan Zentiva

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

In particular, inform your doctor if you are taking:

• other cytostatic agents (antineoplastic agents),
• nalidixic acid (an antibiotic used to treat urinary tract infections),
• cyclosporine (used to prevent transplant rejection, to treat certain skin conditions such as psoriasis and eczema, or to treat rheumatoid arthritis),
• vaccines containing live microorganisms (see Warnings and precautions),
• in children, busulfan (used to treat certain types of cancer).

Pregnancy, breastfeeding, and fertility

Pregnancy and breastfeeding

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

Pregnancy

Treatment with melphalan is not recommended during pregnancy because it may harm the unborn baby. Do not take melphalan if you are planning to have a child. This applies to both men and women. Effective contraception must be used to prevent 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 receiving melphalan. Your doctor will consider the risks and benefits of treatment with melphalan for you and your baby.

Breastfeeding

It is unknown whether melphalan is excreted in breast milk. Do not breastfeed while receiving melphalan.

Fertility

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

Contraception in men and women

Women of childbearing potential must use effective contraception during treatment with melphalan and for at least 6 months after treatment ends.

Men receiving melphalan are advised not to father a child during treatment and for at least 3 months afterwards. Talk to your doctor about using effective and reliable contraceptive methods.

Driving and using machines

The effects of this medicine on the ability to drive or operate machinery have not been studied. This medicine is not expected to affect your ability to drive or use machines.

However, this medicine contains alcohol (ethanol) and propylene glycol, which may affect judgment and reaction capacity (see below).

Melfalan Zentiva contains sodium

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

Melfalan Zentiva contains ethanol

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

This medicine may be harmful to individuals with alcoholism.

The alcohol content should be considered in pregnant women, children, and high-risk groups such as patients with liver disease or epilepsy.

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

The amount of alcohol in this medicine may affect your ability to drive and operate machinery, as it may impair your judgment and reaction time.

Melfalan Zentiva contains propylene glycol

This medicine contains 6.2 g of propylene glycol per vial.

Propylene glycol in this medicine may cause effects similar to those of consuming alcohol and may increase the likelihood of these adverse effects.

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

Use this medicine only if recommended by your doctor.

If you have hepatic or renal impairment, do not take this medicine unless recommended by your doctor. Your doctor may perform additional monitoring while you are taking this medicine.

3. How to administer Melfalan Zentiva

Melfalan will only be administered by doctors or nurses experienced in chemotherapy.

Melfalan is an active cytotoxic agent that should only be used under the supervision of physicians experienced in the administration of such agents.

Route of administration

Melfalan may be administered:

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

How much melfalan to be administered

Your doctor will decide the dose of melfalan you should receive. The treatment dose will depend on:

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

Periodically, your doctor will request blood tests to monitor your blood counts and adjust the dose if necessary.

Risk of blood clots (thromboembolic events)

Your doctor will determine whether 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 venous blood clots.

Use in children

Melfalan is rarely indicated in children. There are no available dosing guidelines for children.

Use in elderly patients

There are no specific dose adjustments required 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 more Melfalan Zentiva than you should

Your doctor will administer the melfalan dose, so it is unlikely that you will receive too much. If you think you have been given too high a dose or a dose has been missed, inform your doctor or nurse.

If you miss a dose of Melfalan Zentiva

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

If you stop treatment with Melfalan 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 adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Serious adverse effects

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

• allergic reaction, signs may include:
  • a rash, lumps or hives on the skin
  • swollen face, eyelids or lips
  • sudden onset of "wheezing" and chest tightness
  • fainting (due to cardiac arrest)
• any sign of fever or infection (sore throat, mouth pain or urinary problems).
• treatment with melphalan may cause a decrease in white blood cells. White blood cells fight infections, and when their numbers are very low, infections may occur.
• any unexpected bruising or bleeding, or feeling extremely tired, dizzy or short of breath, as this could mean that too few blood cells of a certain type are being produced.
• if you suddenly feel unwell (even with a normal temperature).
• if your muscles are painful, stiff or weak and your urine appears darker than normal 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, some of the medicine may leak into surrounding tissues and may damage that tissue. Symptoms of this include mild discomfort at the site, slight redness of the skin or mild rash. In rare cases, necrosis of the surrounding skin, ulcers and damage to deeper tissue may occur.

Consult your doctor if you experience any of the following adverse effects, which may also occur with this medicine:

Very common adverse 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 tingling sensation or feeling of warmth at the site where melphalan was injected
• muscle problems such as atrophy and pain – when melphalan is administered directly into the arm or leg

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

• hair loss at usual doses of melphalan.
• elevated blood levels of a chemical substance called urea in people with kidney problems being treated for myeloma
• a muscle condition that may cause pain, tightness, tingling, burning or numbness called compartment syndrome. This may occur when melphalan is administered directly into the arm or leg.
• inflammation of the soft tissue lining the stomach (gastrointestinal mucosa).

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

• acute kidney failure.

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

• a condition in which you have a low number of red blood cells due to their premature destruction – this may make you feel very tired, short of breath and dizzy, and may cause headaches or yellowing of the skin or eyes
• lung problems that may cause coughing, wheezing and difficulty breathing
• liver problems that may show up in blood tests or cause jaundice (yellowing of the whites of the eyes and skin)
• mouth ulcers with normal doses of melphalan
• skin rashes or itchy skin.

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

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

If any of the adverse effects become severe, or if you notice any adverse effects not listed in this leaflet, please inform your doctor or pharmacist.

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 blood cells that do not function properly. Symptoms of this disease include fatigue, fever, infection and bruising. This disease may also be detected by a blood test that will show whether there is a large number of abnormal blood cells and very few properly functioning ones.

Inform your doctor as soon as possible if you experience any of these symptoms. You may need to stop taking melphalan, but only your doctor can determine whether this is necessary.

Reporting of adverse effects

If you experience any adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Melphalan Zentiva

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the packaging after EXP. The expiry date refers to the last day of the month indicated.

This medicine does not require any special storage temperature.

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

Melphalan must be prepared by a healthcare professional. Once the solution has been reconstituted, it should be used immediately. Any unused medicine and all materials that have come into contact with it must be disposed of in accordance with local regulations.

6. Contents of the pack and other information

Composition of Melfalán Zentiva

The active substance is melphalan. Each vial contains 50 mg of melphalan.

The other components (excipients) are:

Vial with powder: povidone K12 and diluted hydrochloric acid.

Vial with solvent: water for injections, sodium citrate dihydrate, propylene glycol and ethanol.

Melphalan is dissolved in a solvent before administration.

Appearance of the product and contents of the pack

Each pack contains one vial with powder and one vial with solvent.

The vial with powder contains 50 mg of the active substance melphalan as a powder, and the solvent vial contains 10 ml of solvent used to reconstitute (dissolve) the powder.

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

Powder: clear type I glass vial with a bromobutyl rubber stopper coated with Omniflex 3G, and an aluminium flip-off seal with an orange polypropylene cap with a matte finish. The vials may or may not have shrink sleeves.

Each pack contains one vial with 50 mg of melphalan.

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

Each pack contains one 10 ml vial.

Marketing Authorization Holder:

Zentiva, k.s.,

U kabelovny 130,

Prague 10 – Dolní Mecholupy,

102 37 Czech Republic

Manufacturer responsible:

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 European Economic Area member states 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 solution for injection and for infusion EFG

Cyprus: Melphalan Tillomed 50 mg

Greece: Melphalan Tillomed 50 mg

Date of the most recent review of this leaflet: March 2024

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

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This information is intended for healthcare professionals only:

Procedures for proper handling and disposal of cytotoxic medicinal products must be followed:

1. Personnel involved in reconstitution of the medicinal product must be properly trained.
2. Pregnant women must not handle this medicinal product.
3. Personnel must wear appropriate protective clothing, including masks, safety goggles and gloves, when reconstituting the preparation.
4. Any items used for administration or cleaning, including gloves, must be disposed of in waste containers designated for contaminated materials, which must be incinerated at high temperature. Liquid waste may be flushed with abundant water.

In case of accidental eye contact with melphalan, immediately rinse eyes with sodium chloride eye drops or copious amounts of water and seek immediate medical advice. In case of skin contact, immediately wash affected areas with soap and copious amounts of cold water and seek immediate medical advice. Spilled solution must be cleaned up immediately using a damp absorbent paper, which must then be safely disposed of. Contaminated surfaces must be washed thoroughly with abundant water.

Reconstitution

Melphalan must be prepared at room temperature (approximately 25°C) by reconstituting the powder with the provided solvent-diluent.

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

Rapidly add 10 ml of the solvent in a single dose to the vial containing the powder, using a sterile needle and syringe. A 21 gauge or larger needle should be used to pierce the vial stopper during reconstitution. For smooth and effective penetration, the needle must be inserted perpendicularly into the stopper, neither too quickly nor forcefully, and without twisting. Immediately shake the vial vigorously (for approximately 5 minutes) until a clear, particle-free solution is obtained. It is essential to add the diluent rapidly and immediately follow with vigorous shaking to ensure proper dissolution.

Agitation of the formulation produces a significant number of very small air bubbles. These bubbles may persist for 2 to 3 minutes, as the resulting solution is quite viscous. This may make it difficult to assess the clarity of the solution.

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

The reconstituted melphalan solution has limited stability and must be prepared immediately before use.

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

Mixing

Withdraw 10 ml of the previously reconstituted solution with a concentration of 5 mg/ml of anhydrous melphalan and transfer it into an infusion bag containing 100 ml of 0.9% sodium chloride injection solution. Mix well to obtain a nominal concentration of 0.45 mg/ml of anhydrous melphalan.

When further diluted in an infusion solution, melphalan has reduced stability, and the degradation rate increases rapidly with rising temperature. If melphalan is administered at an ambient temperature of approximately 25°C, the maximum time from preparation of the solution to completion of the infusion must not exceed 1.5 hours.

Melphalan is incompatible with infusion solutions containing dextrose, and it is recommended to use only 9 mg/ml (0.9%) sodium chloride injection solution.

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

Disposal

Any unused solution after 1.5 hours must be discarded in accordance with standard guidelines for handling and disposal of cytotoxic medicinal products.

Any unused medicinal product or waste material must be disposed of in compliance with local requirements for cytotoxic medicinal products.