MELPHALAN TARBIS 50 mg POWDER AND SOLVENT FOR INJECTION AND INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Melfalán Tarbis 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.
• 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, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the package leaflet

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

1. What is Melfalán Tarbis 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). It works by reducing the number of abnormal cells produced by the body. This medicine is used to treat cancer.

This medicine is used for:

• Malignant melanoma localized to the limbs (malignant growths present locally in the arms or legs)
• Localized soft tissue sarcoma of the limbs (local neoplasms of the soft tissues of the arms or legs)
• Multiple myeloma: a type of cancer that develops from bone marrow cells called plasma cells. Plasma cells help fight infections and diseases by producing antibodies.
• Advanced neuroblastoma (a cancer that affects the nervous system) in children
• Advanced ovarian carcinoma (ovarian cancer)

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

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

Do not use Melfalán Tarbis:

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

Warnings and precautions

Consult your doctor or nurse before starting to use this medicine if:

• you have recently received or are currently receiving radiation or chemotherapy;
• you have kidney problems;
• you need to be vaccinated. Because melphalan suppresses the body's immune responses, there is a greater susceptibility to infections. Therefore, live vaccines are not recommended;
• you have or have had a blood clot in your leg (thrombosis), lung (pulmonary embolism), or other part of your body;
• you have a disease that increases the risk of blood clots forming in the arteries.

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 (blockage of the main pulmonary artery 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).

If you are not sure if any of these situations apply to you, consult your doctor or pharmacist before being treated with melphalan.

Other medicines and Melfalán Tarbis

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:

• live vaccines (see Warnings and precautions)
• 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 agent used to treat a certain type of cancer).

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 using this medicine.

Menstruation may be absent in female patients, and there is a risk of reduced fertility in male patients. In men, there may be a complete absence of sperm. Therefore, it is recommended that men seek advice on sperm preservation before treatment with melphalan.

Melphalan may have a harmful effect on sperm, eggs, and/or the unborn baby if you or your partner use this infusion solution. Because pregnancy is not desired during treatment with melphalan, it is recommended that both male and female patients use an adequate contraceptive method (contraception). This applies during treatment and for up to three months after its discontinuation.

It is not known whether this medicine is excreted in breast milk. Women using melphalan must not breast-feed.

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 Tarbis contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per vial; this is essentially “sodium-free”

Melfalán Tarbis contains ethanol

This medicine contains 410 mg of alcohol (ethanol) in each vial of solvent, which is equivalent to 0.52 ml. The amount of this medicine in the vial of solvent is equivalent to 10 ml of beer or 4 ml of wine.

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

Melfalán Tarbis contains propylene glycol

This medicine contains 6.24 g of propylene glycol per 10 ml of solvent, which is equivalent to 6.0 ml per vial.

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 to use Melfalán Tarbis

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

This medicine is an active 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 what dose of this medicine 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,
• if 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.

Your doctor will decide 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 a higher risk of developing a blood clot in the veins.

Use in children

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

Use in the elderly

There are no specific dose adjustments for the elderly.

Use in patients with renal impairment

If you have a kidney problem, your doctor will generally give you a lower dose than that given to other adults.

If you are given too much Melfalán Tarbis

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, tell your doctor or nurse.

If you miss a dose of Melfalán Tarbis

Do not take a double dose to make up for missed doses, but follow the regular dosing schedule. Also, consult your doctor.

4. Possible side effects

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

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

• Allergic reaction, the signs may include:
• • skin rash, skin lumps, or hives
  • swelling of the face, eyelids, or lips
  • shortness of breath, wheezing, 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 there is a shortage of a particular type of blood cell
• sudden feeling of illness (even with normal temperature)
• muscle pain, stiffness, or weakness anddarker than usual urine or brown or red-colored urine – when this medicine is administered directly into an arm or leg.
• Tell your doctor immediately if you have symptoms of blood clots in the veins, especially in the legs. The symptoms include swelling, pain, and redness of the leg. Blood clots can travel through the blood vessels to the lungs, causing chest pain and difficulty breathing.

Very common: may affect more than 1 in 10 people

• Fever
• a condition in which the bone marrow stops producing certain types of blood cells (bone marrow depression)
• nausea, vomiting, and diarrhea
• mouth ulcers - at high doses
• hair loss - at high doses
• a feeling of tingling or warmth at the injection site of melphalan
• muscle problems, such as loss of muscle tissue due to muscle disuse (muscle atrophy), increased muscle connective tissue (muscle fibrosis), muscle pain, if melphalan is administered directly into the arm or leg.

Common: may affect up to 1 in 10 people

• hair loss - with the 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

• anemia due to excessive blood destruction (hemolytic anemia)
• lung problems that can cause coughing or wheezing, and difficulty breathing
• jaundice (yellow color in the white of the eyes and skin)
• mouth ulcers - with the usual doses of this medicine
• skin rash or itching

The following side effects may also occur with Melfalán Tarbis:

• leukemia (blood cancer)
• in women: interruption of menstruation (amenorrhea)
• in men: absence of sperm in the semen (azoospermia)
• death of muscle tissue (muscle necrosis)
• breakdown of muscle fibers (rhabdomyolysis)
• formation of a blood clot, called a thrombus, in a deep vein, especially in the legs (deep vein thrombosis) and blockage of a pulmonary artery (pulmonary embolism).
• secondary primary malignant neoplasia

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 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 Tarbis

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

Do not store above 30°C. Do not refrigerate.

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

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 stated.

6. Contents of the pack and further information

Composition of Melfalán Tarbis

The active ingredient is melphalan hydrochloride.

Each vial contains melphalan hydrochloride equivalent to 50 mg of melphalan.

The other components are povidone and hydrochloric acid (for pH adjustment).

This medication must be dissolved in 10 ml of solvent before injection. The solvent contains water for injectable preparations, anhydrous sodium citrate, propylene glycol (E-1520), and ethanol (at 96 percent).

Appearance of the product and packaging content

Each package contains a vial of powder and a vial of 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. The powder is a lyophilized powder or a white to off-white cake, and the solvent is a clear and colorless liquid/solution. After reconstitution with 10 ml of solvent, the resulting solution contains 5 mg/ml of melphalan.

Marketing authorization holder

Tarbis Farma S.L.

Gran Vía Carlos III, 94

08028 Barcelona

Spain

Manufacturer

Pharmadox Healthcare Ltd.

KW20A Kordin Industrial Park

Paola, PLA 3000

Malta.

This medication is authorized in the Member States of the European Economic Area under the following names:

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

Germany: Melphalan Amarox 50 mg powder and solvent for the preparation of an injection/infusion solution

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

Date of the last revision of this leaflet: July/2021

Detailed and updated 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 intended for healthcare professionals only:

Precautions

Melfalán isa cytotoxic agent that must 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

Handling of melphalan formulations should be carried out in accordance with the guidelines for the handling of cytotoxic drugs.

Preparation

This medication should be prepared at room temperature (approximately 25 °C), reconstituting the lyophilized powder with the provided solvent.

Reconstitution:

It is essential that both the lyophilized powder and the provided solvent are at room temperature before starting reconstitution. Warming the diluent in the hand may facilitate reconstitution. 10 ml of this vehicle should be added rapidly as a single quantity to the vial containing the lyophilized powder, and then shaken vigorously (for approximately 1 minute) until a clear 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 6.0 to 7.0.

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

Mixing

Immediately withdraw the reconstituted solution with a concentration of 5 mg/ml of anhydrous melphalan from the reconstituted vial and add it to a perfusion bag containing a 0.9% sodium chloride intravenous infusion using a new 10 ml syringe. Mix this diluted solution well by manual rotation to obtain a nominal concentration of 0.45 mg/ml of anhydrous melphalan.

After reconstitution and dilution, chemical and physical stability has been demonstrated for 1 hour and 15 minutes at 25 °C. Therefore, the total time from reconstitution and dilution to the end of perfusion should not exceed 1 hour and 15 minutes.

From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, the times of use and storage conditions before use are the responsibility of the user. The reconstituted solution should not be refrigerated, as this will cause precipitation.

Melfalán is not compatible with infusion solutions containing dextrose, and it is recommended to use only 0.9% sodium chloride solution for intravenous infusion.