Melphalan zentiva

Package leaflet: Information for the patient

Melphalan Zentiva, 50 mg, powder and solvent for solution for injection / infusion
melphalan
Please read all of this leaflet carefully before 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, please ask your doctor, pharmacist, or nurse.
• If you get any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. 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 using Melphalan Zentiva
3. How to use Melphalan Zentiva
4. Possible side effects
5. How to store Melphalan Zentiva
6. Contents of the pack and other information

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

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

Melphalan Zentiva is used to treat:

• 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.
• Advanced ovarian cancer.
• Neuroblastoma in childhood – a tumour of the nervous system.
• Malignant melanoma – a type of skin cancer.
• Soft tissue sarcoma – a tumour of muscle tissue, fatty tissue, fibrous tissue, blood vessels, or other supportive tissues of the body.

If there is no improvement or if the patient feels worse, contact the doctor.

2. Important information before using Melphalan Zentiva

Do not take Melphalan if any of the following apply to the patient. Inform the doctor if:

• the patient is allergic to melphalan or any of the other ingredients of this medicine (listed in section 6);
• the patient is breastfeeding.

Warnings and precautions
Before starting treatment with melphalan, discuss with the doctor if any of the following apply to the patient:

• the patient is currently undergoing or has recently undergone radiotherapy or chemotherapy;
• the patient has impaired kidney function;
• the patient intends to be vaccinated or has recently been vaccinated. This is because certain vaccines (e.g. against polio, measles, mumps and rubella) may cause infection if administered to a patient during melphalan treatment;
• the patient has or has ever had a blood clot in the leg (deep vein thrombosis), in the lung (pulmonary embolism), or in any other part of the body;
• the patient has a condition that increases the risk of developing arterial blood clots;
• men receiving melphalan must not father children during treatment and for 3 months after its completion.

Melphalan Zentiva and other medicines
Tell the doctor or nurse about all medicines the patient is currently taking or has recently taken, including medicines obtained without a prescription.
In particular, the patient should inform the doctor or nurse if taking any of the following medicines:

• other cytotoxic drugs (chemotherapy);
• nalidixic acid (an antibiotic used to treat urinary tract infections);
• cyclosporine (used to prevent transplant rejection or to treat certain skin diseases such as psoriasis and eczema, or rheumatoid arthritis);
• vaccines containing live organisms (see "Warnings and precautions");
• in children – busulfan (used to treat certain types of cancer).

Pregnancy, breastfeeding and effects on fertility
Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult the doctor before using this medicine.
Pregnancy
Treatment with melphalan during pregnancy is not recommended, as it may cause permanent harm to the unborn child. If the patient is already pregnant, it is important to inform the doctor before receiving melphalan. The doctor will consider the risks and benefits of melphalan treatment for the patient and her child.
Effective contraceptive methods must be used during administration of injections/infusions of this medicine to the patient (or to the partner of the patient) to avoid pregnancy.
Breastfeeding
It is not known whether melphalan passes into human milk. Breastfeeding must not be used during treatment with melphalan.
Fertility
Melphalan may affect the ovaries or sperm, which may lead to infertility (inability to have children). In women treated with Melphalan, absence of menstruation (amenorrhoea) may occur, and in men, complete absence of sperm (azoospermia).
Therefore, men are advised to seek advice about sperm storage before starting treatment.
Contraception in men and women
Men receiving melphalan must not father children during treatment and for 3 months after its completion. If the patient wishes to use an effective method of contraception, this should be discussed with the doctor.
Driving and using machines
The effect on the ability to drive and use machines has not been studied in patients receiving this medicine. Do not assume that this medicine will not affect the ability to drive and use machines.
Melphalan Zentiva contains sodium
The medicine contains 53.5 mg of sodium (the main component of table salt) per vial. This corresponds to 2.7% of the maximum recommended daily dietary sodium intake for adults.
Melphalan Zentiva contains ethanol
The medicine contains 5% ethanol (alcohol), i.e. 0.4 g per vial, equivalent to 10 ml of beer or 4 ml of wine per vial.
Harmful for people with alcoholism.
This should be taken into account in pregnant women, children, and people at high risk, such as patients with liver disease or epilepsy.
The alcohol contained in the medicine may alter the effects of other medicines.
The alcohol contained in the medicine may impair the ability to drive and use machines.
Melphalan Zentiva contains propylene glycol
The medicine contains 6.2 mg of propylene glycol per vial. The propylene glycol contained in this medicine may cause symptoms similar to those after alcohol consumption and may increase the likelihood of adverse reactions.
Inform the doctor if the patient is pregnant, has impaired liver or kidney function, or is taking other medicines containing alcohol.
During treatment with this medicine, the doctor may decide to perform additional monitoring tests in such patients.

3. How to use Melphalan Zentiva

Melphalan will be administered to the patient by doctors or nurses experienced in administering chemotherapy.
Method of administration:
Melphalan may be administered:

• as an intravenous infusion (drip) into a vein,
• into an artery, by perfusion to a specific part of the body.

Dosage of Melphalan Zentiva
The doctor will decide the dose of melphalan to be administered to the patient. The melphalan dose depends on:

• the patient's body weight or body surface area (a calculated measurement taking into account body weight and height),
• other medicines being taken,
• the patient's disease,
• the patient's age,
• presence or absence of impaired kidney function.

During melphalan treatment, the doctor will order regular blood tests. The purpose is to monitor blood cell counts.
Based on the results of these tests, the doctor may adjust the dose given to the patient.
Risk of thrombosis (thromboembolic events)
The doctor will decide whether the patient should receive treatment to prevent blood clots in the veins. This applies during the first 5 months of treatment or if the patient has an increased risk of venous blood clots.
Use in children
Melphalan is rarely used in children. Dosing guidelines for children are not available.
Use in elderly patients
No specific dose adjustment is required in elderly patients.
Use in patients with impaired kidney function
If the patient has kidney disease, the doctor will usually administer a lower dose than in other adults.
Overdose of Melphalan Zentiva
Melphalan will be administered by a doctor; therefore, it is unlikely that the patient will receive too high a dose. If the patient is concerned that an overdose has been administered or a dose has been missed, inform the doctor or nurse immediately.
Missed dose of Melphalan Zentiva
Melphalan will be administered by a doctor, so a missed dose is unlikely. If the patient believes a dose has been missed, the dose should be skipped, and the next dose should be given at the next scheduled time. Do not take a double dose to make up for a missed dose.
Stopping Melphalan Zentiva treatment
If the patient thinks they should stop taking this medicine, they must first consult their doctor.
If there are any further doubts about the use of this medicine, consult the doctor or pharmacist.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
Serious adverse reactions
If the patient experiences any of the following adverse reactions, contact the specialist doctor immediately or go to hospital:
allergic reaction, the symptoms of which may include:

• skin rash, lumps or hives;
• swelling of the face, eyelids or lips;
• sudden wheezing and a feeling of tightness in the chest;
• collapse (due to cardiac arrest);
• symptoms such as fever or infection (sore throat, mouth pain or problems with urination);
• unexplained bruising, bleeding or feeling extremely tired, dizzy or breathless, as this may indicate reduced production of a particular type of blood cells;
• sudden worsening of general condition (even with normal body temperature);
• pain, stiffness or weakness in muscles and darker than usual, brown or red discoloration of urine during administration of melphalan directly into the arm or leg;

Inform the doctor immediately if the patient experiences symptoms of venous thrombosis,
particularly in the legs. These symptoms include swelling, pain and redness in the leg. Thrombi may
travel through blood vessels to the lungs, causing chest pain and breathing difficulties.
Other adverse reactions include:
Very common adverse reactions (may occur in more than 1 in 10 people):

• fever;
• decreased number of blood cells and platelets;
• nausea, vomiting and diarrhoea;
• mouth ulceration (with high doses of melphalan);
• hair loss (with high doses of melphalan);
• tingling or feeling of warmth at the site where melphalan was injected;
• muscle disorders such as atrophy and pain when melphalan is administered directly into the arm or leg.

Common adverse reactions (may occur in up to 1 in 10 people):

• hair loss with normal doses of melphalan;
• high levels of urea in the blood in patients with kidney function disorders being treated for myeloma;
• muscle disorders which may cause pain, pressure, tingling, burning or numbness, known as compartment syndrome. This may occur when melphalan is administered directly into the arm or leg.

Rare adverse reactions (may occur in up to 1 in 1,000 people):

• a condition in which there is a low number of red blood cells due to their premature destruction. This may cause a feeling of severe fatigue, shortness of breath and dizziness, as well as headaches or yellowing of the skin or eyes;
• lung function disorders, which may cause coughing, wheezing and breathing difficulties;
• liver function disorders, which may be evident in blood test results or cause jaundice (yellowing of the whites of the eyes and skin);
• mouth ulceration when using normal doses of melphalan;
• skin rashes or itching.

Frequency unknown (frequency cannot be determined from available data):

• leukaemia (blood cancer);
• in women: cessation of menstruation (amenorrhoea);
• in men: absence of sperm in semen (azoospermia);
• muscle tissue death (muscle necrosis);
• breakdown of muscle fibres (rhabdomyolysis);
• formation of a blood clot (thrombus) in a deep vein, particularly in the legs (deep vein thrombosis), and blockage of one of the pulmonary arteries (pulmonary embolism).

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed
in this leaflet, inform the doctor or pharmacist. Adverse reactions can be reported
directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
By reporting adverse reactions, more information on the safety of the medicine can be collected.

5. How to store 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 cardboard box:
Expiry date (EXP). The expiry date refers to the last day of the stated month.
There are no special storage temperature requirements for this medicine. Store the vial
in its outer packaging to protect it from light.
Melphalan will be prepared for use by healthcare professionals. After preparation,
it should be used immediately. Any unused medicinal product or waste material
should be disposed of in accordance with local regulations.

6. Contents of the pack and other information

What Melphalan Zentiva contains
The active substance is melphalan. Each vial contains 50 mg of melphalan.
The other ingredients are:
Vial with powder: povidone K12 and diluted hydrochloric acid.
Vial with solvent: water for injections, sodium citrate, propylene glycol and 96% ethanol.
Before injection, melphalan is dissolved in the solvent.
What Melphalan looks like and contents of the pack
Each pack contains one vial of melphalan and one 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 solvent used to reconstitute (dissolve) this powder. After reconstitution of the melphalan powder with 10 ml of solvent, the resulting solution contains 5 mg/ml of anhydrous melphalan.
Powder: vial made of colourless type I glass, closed with a bromobutyl rubber stopper coated with a fluorinated polymer “omniflex 3G”, with an aluminium “flip-off” seal and an orange polypropylene cap with a matte finish. The vials may, but do not necessarily, be labelled with a heat-shrinkable label.
Pack size: 1 vial containing 50 mg of melphalan.
Solvent: vial made of colourless type I glass, closed with a bromobutyl rubber stopper, with an aluminium “flip-off” seal and an orange polypropylene cap with a matte finish.
Pack size: 1 vial containing 10 ml.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Zentiva, k.s.
U kabelovny 130
Dolní Měcholupy
102 37 Prague 10
Czech Republic
Importer
SGS Pharma Magyarorszag Kft.
Derkovits Gyula 53
Budapest XIX
1193 Hungary
Tillomed Malta Limited,
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta
This medicinal product is authorised for marketing in the Member States of the European Economic Area under the following names:

Information intended solely for medical professionals:

The proper handling and disposal procedures for cytotoxic medicinal products must be strictly observed:

1. Personnel must be trained in the techniques for reconstitution of the medicinal product.
2. Pregnant women should not be involved in handling this medicinal product.
3. During reconstitution, personnel must wear appropriate protective clothing, including a face mask, protective goggles, and gloves.
4. All materials used for administration or cleaning, including gloves, must be disposed of in containers designated for contaminated waste, to be incinerated at high temperature.

In case of accidental contact of melphalan with the eyes, immediately rinse the eyes thoroughly with physiological saline solution for eye irrigation or with large amounts of water and seek immediate medical advice. In case of skin contact, the affected areas must be washed immediately with large amounts of cold water and soap, and immediate medical advice must be sought. Any spilled solution must be wiped up immediately using a damp paper towel, which must then be safely disposed of. Contaminated surfaces must be cleaned thoroughly with large amounts of water.

Reconstitution
Melphalan Zentiva should be prepared at room temperature (approximately 25°C) by reconstituting the powder with the provided solvent.
It is important that both the powder and the provided solvent are at room temperature (approximately 25°C) before reconstitution is initiated.
Rapidly add the full 10 ml of solvent in one step to the vial containing the powder using a sterile needle and syringe. A needle of size 21 or larger should be used to pierce the vial stopper during reconstitution. To effectively insert the needle, it should be inserted perpendicularly into the stopper, not too quickly or forcefully, and without rotating it. Immediately thereafter, shake the vial vigorously (for approximately 5 minutes) until a clear solution is obtained, free from visible solid particles. For proper dissolution of the powder, it is essential to add the solvent rapidly and then immediately shake the vial vigorously.
Shaking the preparation results in the formation of 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 assessment of solution clarity difficult.
Each vial must be reconstituted separately in the same manner. The resulting solution contains an equivalent of 5 mg of melphalan per ml of anhydrous melphalan. Failure to follow the above steps may result in incomplete dissolution of melphalan.

The melphalan solution has limited stability and must be prepared immediately prior to use. The reconstituted solution must not be stored in a refrigerator, as this will cause precipitation.

Dilution
Transfer 10 ml of the above-reconstituted solution at a concentration of 5 mg/ml anhydrous melphalan into an infusion bag containing 100 ml of 0.9% sodium chloride injection solution. Mix this diluted solution thoroughly to achieve a nominal concentration of 0.45 mg/ml anhydrous melphalan.
Further dilution of the infusion solution reduces the stability of Melphalan Zentiva, and decomposition accelerates with increasing temperature.
When administering Melphalan Zentiva as an infusion at room 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 Zentiva is incompatible with infusion solutions containing dextrose, and the exclusive use of 9 mg/ml (0.9%) sodium chloride injection solution is recommended.
If any cloudiness or crystals appear in the reconstituted or diluted solution, the product must be discarded.

Disposal
Any solution not used within 1.5 hours must be disposed of 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 accordance with local regulations governing cytotoxic medicinal products.