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

Introduction

Package Leaflet: Information for the User

Melfalán Hikma 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 or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

This medicine contains the active substance called melphalan, which belongs to a group of medicines called cytotoxics (also known as chemotherapy). This medicine is used to treat cancer. It works by reducing the number of abnormal cells produced by the body

This medicine is used for:

• Multiple myeloma- a type of cancer that develops from cells in the bone marrow called plasma cells. Plasma cells help fight infections and diseases by producing antibodies.
• Ovarian canceradvanced
• Neuroblastomain children- cancer that affects the nervous system
• Malignant melanoma– skin cancer
• Soft tissue sarcoma– muscle, fat, fibrous tissue, blood vessels or other supporting tissue cancer

Ask your doctor if you want more information about these diseases.

2. What you need to know before you use Melfalán Hikma

Do not use Melfalán Hikma:

• if you are allergic to melphalan or any of the other ingredients of this medicine (listed in section 6).
• if you are breast-feeding (see section “Pregnancy, breast-feeding and fertility”).

Do not use melphalan if any of the above applies to you. If you are unsure, consult your doctor or nurse before taking Melfalán Hikma.

Warnings and precautions

Consult your doctor or nurse before receiving this medicine if:

• you have recently received or are currently receiving radiation or chemotherapy;
• you have kidney problems;
• you are going to receive a vaccine or have been vaccinated recently (see “Vaccines”),
• you are using combined oral contraceptives (the pill). This is due to the increased risk of venous thrombosis (a blood clot that forms in a vein and travels to another site) in patients with multiple myeloma (see “Pregnancy, breast-feeding and fertility”).

Melphalan may increase the risk of developing other types 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 should carefully evaluate the benefits and risks when prescribing melphalan.

Thromboembolic events

There is an increased risk of deep vein thrombosis (formation of a blood clot called a thrombus within a deep vein, predominantly 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 lungs) when melphalan is used in combination with other medicines that may affect the functioning of your immune system (such as lenalidomide/thalidomide) and others that may increase the benefits of treatment with melphalan (such as prednisone/dexamethasone).

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

Reduction of white blood cells and blood platelets

An increase in hematologic toxicities, such as neutropenia (decrease in the number of white blood cells, which can increase the risk of infection) and thrombocytopenia (low platelet count, which can cause bruising and bleeding) has been observed when melphalan is used in combination with other medicines that may affect the way your immune system works (such as lenalidomide/thalidomide) and others that may increase the benefits of treatment with melphalan (such as prednisone/dexamethasone).

If you are unsure whether any of these situations apply to you, consult your doctor or pharmacist before being treated with melphalan.

Other medicines and Melfalán Hikma

Tell your doctor if you are taking, have recently taken, or might take any other medicines.

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

• other cytotoxic medicines (chemotherapy)
• live vaccines (see “Vaccines”)
• nalidixic acid (an antibiotic used to treat urinary tract infections)
• cyclosporin (used to prevent organ or tissue rejection after a transplant or to treat certain skin diseases such as eczema and psoriasis or to treat rheumatoid arthritis)
• in children, busulfan (another chemotherapeutic drug used to treat a certain type of cancer).

Vaccines and Melfalán

If you are going to be vaccinated, inform your doctor or nurse before receiving the vaccine. This is because some vaccines (such as polio, measles, mumps, and rubella vaccines) may cause you to become infected if administered while you are being treated with this medicine.

Pregnancy, breast-feeding and fertility

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 taking this medicine.

Do not breast-feed while being treated with this medicine. Consult your doctor or obstetrician.

Pregnancy

Treatment with melphalan is not recommended during pregnancy because it may cause permanent damage to the fetus. If you are already pregnant, it is essential that you discuss the risks and benefits of treatment with melphalan with your doctor. Your doctor will evaluate the risks and benefits of treatment with melphalan for you and your child.

Fertility/contraception for men and women

Do not take melphalan if you intend to have a child. This applies to both men and women. This medicine may damage sperm or eggs, which can cause infertility (inability to have a child). In women, it may stop menstruation (amenorrhea), and in men, it may cause a complete absence of sperm (azoospermia). Due to the possibility of azoospermia as a result of treatment with melphalan, men are advised to consult about sperm preservation before treatment.

Men treated with melphalan should not father children during treatment and up to 3 months after treatment has finished. Effective contraceptive methods should be used to avoid pregnancy during this period.

If you are a woman, you must take effective contraceptive precautions to avoid pregnancy while receiving this treatment and for up to 6 months after treatment.

Consult your doctor.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed in patients taking this medicine. It is not expected that this medicine will affect the ability to drive or use machines.

Melfalán Hikma contains sodium

This medicine contains 2.04 mmol (47 mg) of sodium per vial of solvent. This is equivalent to 2.4% of the maximum recommended daily dietary intake of sodium for an adult.

Melfalán Hikma contains ethanol

This medicine contains 0.4 g of alcohol (ethanol) in each vial of solvent, which is equivalent to 5% of ethanol (alcohol). The amount in one vial of this medicine is equivalent to 10 ml of beer or 4.2 ml of wine. Harmful for individuals suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children, and high-risk groups such as patients with liver disease or epilepsy.

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

The amount of alcohol in this medicine may affect your ability to drive or use machines.

Melfalán Hikma contains propylene glycol

This medicine contains 6.3 g of propylene glycol per vial of solvent. The propylene glycol in this medicine may have the same effects as drinking alcohol and increase the likelihood of side effects.

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

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

3. How to use Melfalán Hikma

This medicine should only be prescribed by a specialist doctor with experience in the treatment of cancer.

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

This medicine can be administered:

• as an intravenous infusion
• as an infusion into a specific part of the body through an artery.

Your doctor will decide the dose of this medicine that should be administered. The dose of this medicine 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,
• whether you have kidney problems.

During treatment with this medicine, your doctor will regularly perform blood tests. This is done to count the number of cells in your blood. Occasionally, your doctor may change your dose as a result of these tests.

Use in children

Melphalan is rarely used in children. Dosage guidelines for children are not available.

Use in elderly patients

There are no specific dose adjustments for elderly patients.

Use in patients with renal impairment

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

If you receive more Melfalán Hikma than you need

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

If you miss a dose of Melfalán Hikma

Your doctor will administer the dose of melphalan, so it is unlikely that you will miss a dose.

If you think a dose has been missed, the next dose will be administered at the next scheduled time. Do not use a double dose to make up for missed doses.

If you stop using Melfalán Hikma

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

If you have any further questions on 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.

Tell your doctor immediately if you experience signs or symptoms of thromboembolism (such as difficulty breathing, chest pain, swelling of arms or legs). If you experience a thromboembolic event, your doctor may decide to interrupt treatment and initiate standard anticoagulation therapy. Once the thromboembolic episode has been controlled, your doctor will decide whether to restart treatment with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone.

If you experience any of the following, contact your specialist doctor or go to the hospital immediately:

• Allergic reaction, the signs may include:
• • skin rash, lumps on the skin or hives
  • swelling of the face, eyelids or lips
  • shortness of breath and sudden chest tightness
  • collapse (due to cardiac arrest)
• signs of fever or infection (sore throat, mouth ulcers or urinary problems)
• unexpected bruising or bleeding, or feeling extremely tired, dizzy or short of breath, as this could mean that you have a low level of a particular type of blood cell
• sudden feeling of illness (even with normal temperature)
• pain, stiffness or weakness of the muscles anddarker than usual urine, or brown or red-colored urine – when this medicine is administered directly into an arm or leg.

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

Very common: may affect more than 1 in 10 people

• a decrease in the number of blood cells and platelets
• nausea, vomiting, and diarrhea
• mouth ulcers - with high doses of this medicine
• hair loss - with high doses of this medicine
• a feeling of tingling or warmth at the injection site of melphalan
• muscle problems, such as pain and loss of muscle mass, if melphalan is administered directly into the arm or leg.

Common: may affect up to 1 in 10 people

• hair loss - with usual doses of this medicine
• 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, tension, tingling, burning, or numbness, called compartment syndrome. This can occur when this medicine is administered directly into an arm or leg

Rare: may affect up to 1 in 1000 people

• Disease consisting of a low red blood cell count due to increased premature breakdown of these cells - this can cause fatigue, fever, dizziness, and yellowing of the skin or eyes
• lung problems that can cause coughing or wheezing, and difficulty breathing
• Liver problems that can be seen in blood tests or cause jaundice (yellowing of the skin and eyes)
• mouth ulcers - with usual doses of this medicine
• skin rash or itching

Side effects of unknown frequency (cannot be estimated from the available data):

• death of muscle tissue (muscle necrosis), muscle breakdown (rhabdomyolysis) leading to muscle weakness and numbness.
• leukemia (blood cancer)
• in women: interruption of menstruation (amenorrhea)
• in men: absence of sperm in the semen (azoospermia)
• deep vein thrombosis (formation of a blood clot (thrombus) in a deep vein, predominantly in the leg) and pulmonary embolism (a blockage of the pulmonary artery or its branches by a blood clot that breaks loose and travels to the lungs).
• increased risk of having a second, unrelated cancer in the future

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 function properly. The symptoms of this disease include fatigue, fever, infection, and bruising. This disease can also be detected by a blood test that shows whether there are a large number of cells in the blood that do not function properly and very few cells that do.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Melfalán Hikma

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

Do not store above 25°C.

Keep the vial in the outer packaging to protect it from light. Do not refrigerate.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date is the last day of the month shown.

This medicine will be prepared for use by a healthcare professional. Once prepared, it should be used immediately and should not be stored or refrigerated.

6. Contents of the pack and other information

Composition of Melfalán Hikma

• The active ingredient is melphalan. Each vial of Melfalán Hikma contains 50 mg of melphalan (in the form of melphalan hydrochloride).
• The other components are povidone K12 and hydrochloric acid.
• Melfalán Hikma must be dissolved in 10 ml of solvent before injection. The solvent contains water for injectable preparations, sodium citrate, propylene glycol (E-1520), and ethanol.

Appearance of the product and packaging content

Each package contains a vial of white to off-white powder and a vial of colorless and transparent solvent. The powder vial contains 50 mg of the active ingredient melphalan in powder form, and the solvent vial contains 10 ml of a solvent for reconstitution (dissolving) the powder. After reconstitution with 10 ml of the solvent, the resulting solution contains 5 mg/ml of anhydrous melphalan.

Marketing authorization holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó n.º 8, 8A e 8B, Fervença

2705-906 Terrugem SNT

Portugal

Manufacturer

Thymoorgan Pharmazie Gmbh

Schiffgraben, 23

Vienenburg, Goslar, Lower Saxony

Germany

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

Hikma España, S.L.U.

Calle Anabel Segura nº11, Edificio A, planta 1ª, oficina 2

28108 - Alcobendas, Madrid

Spain

This medication is authorized in the member states of the European Economic Area under the following names:

Austria/Germany: Melphalan Hikma 50 mg Powder and solvent for solution for injection/infusion

Belgium: Melphalan Hikma 50 mg Powder and solvent for solution for injection/infusion

Melfalan Hikma 50 mg powder and solvent for solution for injection/infusion

Melphalan Hikma 50 mg Powder and solvent for injectable solution/for perfusion

France: Melphalan Hikma 50 mg/10 mL, powder and solvent for injectable solution/for perfusion

Italy: Melfalan Hikma

Netherlands: Melfalan Hikma 50 mg, powder and solvent for solution for injection/infusion

Portugal: Melfalano Hikma

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

United Kingdom (Northern Ireland): Melphalan 50 mg Powder and solvent for solution for injection/infusion

Date of the last revision of this prospectus: February 2022

Detailed information about 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 intended only for healthcare professionals:

Precautions

Melfalán is a cytotoxic agent that should be used under the direction of physicians with experience in the administration of such agents.Caution should be exercised during handling and preparation. The use of gloves and other protective clothing is recommended to avoid skin contact.

Safe handling of melphalan

The handling of melphalan formulations should be adjusted to the guidelines for the handling of cytotoxic drugs.

Preparation

Melfalán Hikma injectable/infusion solution should be prepared at room temperature(approximately 25 °C), reconstituting the lyophilized powder with the provided solvent.

It is essential that both the lyophilized powder and the provided solvent are at room temperature before starting the reconstitution. Warming the diluent in the hand may facilitate reconstitution. 10 ml of this vehicle should be added quickly as a single quantity to the vial containing the lyophilized powder, and immediately shaken vigorously (for approximately 1 minute) until a clear, colorless solution without visible particles is obtained. Each vial should be reconstituted individually in this way. The resulting solution contains the equivalent of 5 mg/ml of anhydrous melphalan and has a pH of approximately 6.5.

Melfalán is not compatible with infusion solutions containing dextrose, and it is recommended to use exclusively9 mg/ml (0.9%) sodium chloride solution for intravenous infusion.

The chemical and physical stability of melphalan in use is limited, and the solution should be prepared immediately before use. The reconstituted solution (5 mg/ml) should be used immediately, and the diluted solution should be administered completely within 1.5 hours after reconstitution.

The disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Administration

Unless regional arterial perfusion is indicated, melphalan is exclusively for intravenous use.

For intravenous administration, it is recommended to inject the melphalan solution slowly into a rapid administration infusion solution through a disinfected injection port.

If direct injection into a rapid administration infusion is not suitable, the melphalan solution can be administered diluted in an infusion bag.

Care should be taken to avoid possible extravasation of melphalan, and in the case of poor peripheral venous access, the use of a central venous catheter should be considered. If a high dose of melphalan is administered with or without autologous bone marrow transplantation, administration through a central venous catheter is recommended.

For regional arterial perfusion, the detailed methodology should be consulted in the literature.

For more information, consult the product's technical data sheet.