Phelinun

Package leaflet: Information for the user

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion

melphalan
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• 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 this leaflet

1. What PHELINUN is and what it is used for
2. What you must know before being given PHELINUN
3. How to use PHELINUN
4. Possible side effects
5. How to store PHELINUN
6. Contents of the pack and other information

1. What PHELINUN is and what it is used for

PHELINUN contains the active substance called melphalan, which belongs to a group of medicines known as cytotoxic agents (also called chemotherapy). It works by reducing the number of certain cells.
PHELINUN may be used alone or in combination with other medicines or with total body irradiation for the treatment of:

• various types of bone marrow cancer: multiple myeloma, acute lymphoblastic leukaemia (also known as acute lymphocytic leukaemia, ALL) and acute myeloid leukaemia (AML);
• malignant lymphoma (Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), a cancer affecting a type of white blood cells called lymphocytes (cells that fight infections);
• neuroblastoma, a type of cancer developing from abnormal nerve cells within the body;
• advanced ovarian cancer;
• advanced breast cancer.

PHELINUN is also used, in combination with other cytotoxic medicines, as a conditioning agent prior to haematopoietic stem cell transplantation for the treatment of blood cancers in adults as well as cancers and non-cancerous blood disorders in the paediatric population.

2. What you should know before being given PHELINUN

If you have any doubts, do not hesitate to ask your doctor for advice.
You must not be given PHELINUN

• if you are allergic to melphalan or to any of the other ingredients of this medicine (listed in section 6);
• if you are pregnant (only regarding treatment prior to haematopoietic stem cell transplantation) or if you are breastfeeding (see section 2 “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
If you are about to undergo treatment with melphalan, careful blood monitoring will be performed, as this medicine is a potent cytotoxic agent that causes a significant reduction in blood cells.
Before treatment with melphalan, inform your doctor if any of the following conditions apply to you:

• if you have recently undergone radiotherapy or taken anticancer medicines, as these often reduce blood cell levels;
• if you show signs of infection (fever, chills, etc.). During treatment with melphalan, your doctor may prescribe antimicrobial medicines such as antibiotics, antifungals or antivirals to prevent infections. Your doctor may also consider administering blood-derived products (e.g. red blood cells and platelets);
• if you have kidney problems or renal failure (when kidneys do not function adequately). In such cases, the dose of PHELINUN must be reduced;
• if you have ever had a blood clot in the veins (thrombosis). The use of melphalan in combination with lenalidomide and prednisone or thalidomide or dexamethasone may increase the risk of developing blood clots. Your doctor may decide to administer medicines to prevent this.

During treatment with melphalan, adequate hydration and forced diuresis (large volume of fluids administered intravenously via infusion) are recommended.
To prevent and treat infections, antimicrobial medicines will be administered.
To prevent and treat gastrointestinal complications, antiemetic medicines will be administered.
Children and adolescents
Children and adolescents may be at higher risk of developing severe respiratory and gastrointestinal complications. Inform your doctor or nurse immediately if you experience any respiratory or gastrointestinal symptoms.
Melphalan must not be used as a conditioning agent prior to haematopoietic stem cell transplantation in adolescents over 12 years of age with acute myeloid leukaemia.
The safety and efficacy of melphalan as a conditioning agent prior to haematopoietic stem cell transplantation in children under 2 years of age for the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia have not been established.
Other medicines and PHELINUN
Inform your doctor or nurse if you are taking or have recently taken any other medicines, including those not requiring a prescription.
In particular, inform your doctor or nurse if you are taking any of the following medicines:

• other cytotoxic medicines (chemotherapy);
• nalidixic acid (an antibiotic used to treat urinary tract infections). In children, this may cause fatal haemorrhagic enterocolitis when administered in combination with melphalan;
• busulfan (used to treat a certain type of cancer). In children, administration of melphalan less than 24 hours after the last oral dose of busulfan has been reported to affect toxicity development;
• if you are about to receive or have recently received a vaccination, as some live attenuated vaccines (such as those for polio, measles, mumps and rubella) may cause infection during treatment with melphalan.

Cases of impaired renal function have been reported when cyclosporine is used to prevent graft-versus-host disease following haematopoietic stem cell transplantation.
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before receiving this medicine.
Pregnancy
Haematopoietic stem cell transplantation is contraindicated in pregnant women. For other indications, treatment with melphalan is not recommended during pregnancy because it may cause permanent harm to the foetus.
If pregnancy has already occurred, it is important to consult your doctor before receiving melphalan.
Your doctor will need to evaluate, together with you, the risks and benefits of melphalan treatment for you and your baby.
Effective contraceptive measures must be used during treatment with melphalan and for 6 months after treatment to avoid pregnancy.
Breastfeeding
It is not known whether melphalan passes into breast milk. Do not breastfeed during treatment with PHELINUN.
Fertility
Melphalan may affect the ovaries or sperm, causing infertility (inability to have children).
In women, ovulation and consequently the menstrual cycle may cease (amenorrhoea). In men, based on animal studies, absence or low numbers of viable sperm may occur. Therefore, men are advised to seek counselling about sperm preservation before treatment.
Male and female contraception
Men and women undergoing treatment with melphalan are advised to use effective contraception during treatment and for 6 months after treatment.
Driving and using machines
This medicine may cause nausea and vomiting, which could impair your ability to drive or operate machinery. This medicine also contains alcohol, which may affect children and adolescents (see section 2 “PHELINUN contains ethanol (alcohol)”).
PHELINUN contains ethanol (alcohol)
This medicine contains 0.4 g of alcohol (ethanol) in each vial of solvent, equivalent to 42 mg/ml (0.42% weight/volume). The amount of this medicine in the solvent vial corresponds to 10 ml of beer or 4 ml of wine.
Adults
The amount of alcohol contained in this medicine is not sufficient to have negative effects in adults.
The alcohol content in this medicine may alter the effect of other medicines.
Consult your doctor or pharmacist if you are taking other medicines.
If you are pregnant or breastfeeding, consult your doctor or pharmacist before using this medicine. See also the information above under “Pregnancy”.
If you are alcohol-dependent, consult your doctor or pharmacist before using this medicine.
Children and adolescents
The alcohol contained in this formulation may affect children and adolescents, including causing drowsiness and behavioural changes. It may also impair concentration and ability to participate in physical activities. If you have epilepsy or liver problems, consult your doctor or pharmacist before using this medicine.
The amount of alcohol contained in this medicine may alter the effect of other medicines.
Consult your doctor or pharmacist if you are taking other medicines.
If you are pregnant or breastfeeding, consult your doctor or pharmacist before using this medicine. See also the information above under “Pregnancy”.
If you are alcohol-dependent, consult your doctor or pharmacist before using this medicine.
PHELINUN contains propylene glycol
This medicine contains 6.2 g of propylene glycol in each 10 ml of solvent, equivalent to 0.62 g/ml.
If your child is under 5 years of age, consult your doctor or pharmacist before administering this medicine, especially if using other medicines containing propylene glycol or alcohol.
If you are pregnant or breastfeeding, do not take this medicine unless recommended by your doctor. See also the information above under “Pregnancy”.
If you have liver or kidney disease, do not take this medicine unless recommended by your doctor. Your doctor may perform additional monitoring during treatment.
The propylene glycol in this medicine may have effects similar to those of alcoholic beverages and may therefore increase the likelihood of adverse effects.
Use this medicine only if recommended by a doctor. Your doctor may perform additional monitoring during treatment.
PHELINUN contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. essentially “sodium-free”.

3. How PHELINUN is administered

PHELINUN will always be administered by a healthcare professional experienced in the use of anticancer medicines or in stem cell transplantation.
Your doctor will calculate the dose of PHELINUN based on your body surface area or body weight, your condition, and your kidney function.
When PHELINUN is used as a treatment prior to haematopoietic stem cell transplantation, it is always administered in combination with other medicinal products.

Use in adults
The recommended dose range is between 100 and 200 mg/m² of total body surface area.
The dose may be divided equally over 2 or 3 consecutive days.

Use in the paediatric population
The dosing regimen is as follows: a dose between 100 and 240 mg/m² of total body surface area.
The dose may be divided equally over 2 or 3 consecutive days.

Use in patients with reduced renal function
In general, the dose will be lower depending on the severity of the kidney problem.

Administration
PHELINUN is administered by intravenous infusion (drip into a vein).
If PHELINUN is accidentally injected outside the vein into the surrounding tissue or leaks out of the vein into the surrounding tissue (extravasation), administration of PHELINUN must be stopped immediately, as it may cause severe tissue damage, typically accompanied by stinging and burning pain.
If patients are unable to report pain, other signs such as redness and swelling at the injection site should be carefully observed.

If you are given more PHELINUN than you should receive
If you think that you have been given too high a dose or that a dose has been missed, inform your doctor or nurse.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Contact your doctor, pharmacist, or nurse immediately if you experience any of the following side effects.

Serious side effects
If you experience any of the following side effects, consult a specialist or go to hospital immediately:

• Graft-versus-host disease following haematopoietic stem cell transplantation (when transplanted cells attack the body, potentially fatal)
• Decrease in circulating blood cells and platelets, which may lead to anaemia (reduction in red blood cells), abnormal bleeding, bruising
• Infection, sometimes severe and potentially fatal
• Gastrointestinal bleeding
• Dysfunction of two or more organ systems causing discomfort and potentially life-threatening
• Disorders of female reproductive function that may cause ovarian dysfunction and premature menopause
• In men: absence of sperm in semen (azoospermia)
• Septic shock
• Progression, relapse or recurrence of cancer, development of a new cancer
• Leukaemia, myelodysplastic syndrome (a specific type of blood cancer)
• Respiratory disorders: respiratory failure, shortness of breath (acute respiratory distress syndrome), lung inflammation (pneumonia, idiopathic pneumonia syndrome), thickening of lung tissue (interstitial lung disease, pulmonary fibrosis), bleeding in the lungs
• Formation of blood clots in small blood vessels throughout the body, damaging brain, kidneys and heart
• Bleeding in the brain
• Liver disorders: toxic liver injury, blockage of a hepatic vein
• Kidney damage (acute kidney injury, nephrotic syndrome), reduced kidney function
• Allergic reaction; signs may include hives, swelling, skin rash, loss of consciousness, difficulty breathing, low blood pressure, heart failure and death
• Collapse (due to cardiac arrest)
• A condition in which red blood cells are destroyed prematurely, causing extreme tiredness, shortness of breath and dizziness, possibly leading to headache or yellowing of the skin or eyes
• Cardiovascular disorders: changes and abnormalities in the heart's pumping ability causing fluid retention, shortness of breath, feeling of fatigue (heart failure, cardiomyopathy), and inflammation around the heart (pericardial effusion)
• High blood pressure in the lung arteries
• Severe inflammatory and immunological complications (haemophagocytic lymphohistiocytosis)
• Severe skin damage (e.g. lesions, blisters, peeling in severe cases) which may affect the entire body surface and may be potentially fatal (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Bleeding
• Formation of blood clots in a deep vein, particularly in the legs (deep vein thrombosis) and blockage of the pulmonary artery (pulmonary embolism)

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

• Alopecia (hair loss), at high doses

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

• Nausea
• Vomiting
• Diarrhoea
• Inflammation inside and around the mouth (stomatitis)
• Fever, chills
• Absence of menstrual periods (amenorrhoea)
• Alopecia (hair loss), at normal doses

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

• Skin disorders: skin redness with small confluent pustules (maculopapular rash)
• Patients with severe blood disorders may experience a sensation of warmth or tingling

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

• Itching
• Liver problems that may appear in blood tests or cause jaundice (yellowing of the whites of the eyes and skin)

Frequency not known (cannot be estimated from available data)

• Inflammation of the bladder with blood in the urine
• Elevated creatinine levels in the blood

Other side effects in children and adolescents
Children and adolescents may be more likely to develop severe respiratory and gastrointestinal complications.

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

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store PHELINUN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the carton after "Exp.". The expiry date refers to the last day of that month.
Do not refrigerate.
Keep the vials in the outer cardboard box to protect the medicine from light.
After reconstitution and dilution, the product is stable for 1 hour and 30 minutes at 25 °C. Therefore, the total time from reconstitution and dilution to completion of infusion must not exceed 1 hour and 30 minutes.
From a microbiological standpoint, the product should be used immediately.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What PHELINUN contains

• The active substance is melphalan. One vial of powder contains 50 mg of melphalan (as melphalan hydrochloride). After reconstitution with 10 ml of solvent, the final concentration of the solution is 5 mg/ml of melphalan.
• The other components are:
  Powder: hydrochloric acid (E507) and povidone (E1201)
  Solvent: water for injections, propylene glycol (E1520), ethanol, and sodium citrate (E331) (see section 2).

Description of the appearance of PHELINUN and contents of the pack
PHELINUN is a powder and solvent for concentrate for solution for infusion.
The powder is supplied in a clear glass vial containing a white to pale yellow powder or agglomerate. The solvent is a clear, colourless solution contained in a clear glass vial.
Each pack of PHELINUN contains: one vial with 50 mg of powder (melphalan) and one vial with 10 ml of solvent.

Marketing Authorisation Holder
ADIENNE S.r.l. S.U.
Via Galileo Galilei, 19
20867 Caponago (MB)
Italy
Tel: +39 0240700445
E-mail: [email protected]

Manufacturer
NERPHARMA S.R.L.
Viale Pasteur, 10
20014 Nerviano (MI)
Italy
Tel: +39 0331 581111

Marketing Authorisation Holder and Manufacturer
ADIENNE S.r.l. S.U.
Via Galileo Galilei, 19
20867 Caponago (MB) Italy
Tel: +39-02 40700445
[email protected]

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu

The following information is intended exclusively for healthcare professionals:

PHELINUN 50 mg powder and solvent for concentrate for solution for infusion
As with any high-dose chemotherapy, the preparation and handling of this product require specific precautions to ensure the protection of both healthcare personnel and the surrounding environment, taking into account the safety conditions required for the patient.
In addition to standard precautions aimed at maintaining sterility of injectable preparations, the following measures must be taken:

• Wear long-sleeved clothing with tight cuffs to prevent splashing of solution onto the skin;
• Wear a disposable surgical mask and safety goggles;
• Wear disposable gloves after washing hands under aseptic conditions;
• Prepare the solution in a dedicated area;
• Interrupt the infusion in case of extravasation;
• Dispose of materials used in solution preparation (syringes, gauzes, drapes, vial) in designated containers;
• Destroy contaminated waste;
• Handle excreta and vomit with caution.

If PHELINUN comes into accidental contact with the skin, the affected areas must be washed immediately and thoroughly with soap and water.
In case of accidental contact with eyes or mucous membranes, rinse thoroughly with abundant water.
Avoid inhalation of the product.
Pregnant women must not handle cytotoxic drugs.

Dosage
Adults
Multiple myeloma, malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma), acute
lymphoblastic and acute myeloblastic leukemia (ALL and AML), ovarian cancer and high-dose
breast adenocarcinoma
The dosage regimen is as follows: a dose between 100 and 200 mg/m² of total body surface area (approximately 2.5–5.0 mg/kg body weight). The dose may be equally divided over 2 or 3 consecutive days. An autologous hematopoietic stem cell transplant is required following doses exceeding 140 mg/m² of total body surface area.

Hematological malignancies prior to allogeneic hematopoietic stem cell transplantation
The recommended dose is 140 mg/m² as a single daily infusion or 70 mg/m² once daily for two consecutive days.

Pediatric population
High-dose acute lymphoblastic and acute myeloblastic leukemia
The dosage regimen is as follows: a dose between 100 and 200 mg/m² of total body surface area (approximately 2.5–5.0 mg/kg body weight). The dose may be equally divided over 2 or 3 consecutive days. An autologous hematopoietic stem cell transplant is required following doses exceeding 140 mg/m² of total body surface area.

Infantile neuroblastoma
The recommended dose to consolidate a response achieved with conventional therapy is a single dose between 100 mg/m² and 240 mg/m² of total body surface area (sometimes equally divided over 3 consecutive days), together with an autologous hematopoietic stem cell transplant. The infusion may be used alone or in combination with radiotherapy and/or other cytotoxic agents.

Hematological diseases prior to allogeneic hematopoietic stem cell transplantation
The recommended dose is as follows:

• Malignant hematological diseases: 140 mg/m² as a single daily infusion;
• Non-malignant hematological diseases: 140 mg/m² as a single daily infusion or 70 mg/m² once daily for two consecutive days.

Thromboembolic complications
Antithrombotic prophylaxis should be administered for at least the first 5 months of treatment, particularly in patients at higher risk of thrombosis. The decision to implement antithrombotic prophylactic measures should be made after a thorough assessment of the individual patient's underlying risks (see sections 4.4 and 4.8).
It is recommended to ensure adequate hydration and forced diuresis in patients, as well as prophylactic administration of anti-infective agents (against bacteria, fungi, or viruses) (see section 4.4).
Pretreatment with cyclophosphamide appears to reduce the severity of gastrointestinal damage induced by high-dose PHELINUN; consult the literature for details (see section 4.8).
Prophylactic measures such as administration of anti-infective agents may be beneficial (see section 4.8).
Graft-versus-host disease (GvHD) may be prevented by using immunosuppressive therapy as prophylaxis after hematopoietic stem cell transplantation (see section 4.8).

Special populations
Elderly
There are no specific dosage recommendations for administration of PHELINUN in the elderly.
However, conventional doses of melphalan are often administered to elderly patients.
Experience with high-dose melphalan in elderly patients is limited. Therefore, adequate performance status and organ function should be carefully considered before administering high-dose melphalan to elderly patients.

Renal impairment
Dosage adjustment is required in patients with renal impairment (see section 4.4).
Melphalan clearance, although variable, may be reduced in patients with impaired renal function.
High-dose melphalan combined with hematopoietic stem cell rescue has been successfully used even in dialysis-dependent patients with end-stage renal failure.
As a general guide, for high-dose melphalan treatment without hematopoietic stem cell transplantation in patients with moderate renal impairment (creatinine clearance 30–50 ml/min), a 50% dose reduction is typically used. High-dose melphalan (doses exceeding 140 mg/m²) without hematopoietic stem cell transplantation must not be used in patients with more severe renal impairment.
For intravenous high-dose melphalan (100–240 mg/m² of total body surface area), the need for dose reduction depends on the degree of renal impairment, whether hematopoietic stem cells are to be reinfused, and therapeutic necessity. Melphalan injection must be administered with hematopoietic stem cell rescue at doses exceeding 140 mg/m².

Hepatic impairment
No dosage adjustment is required in patients with mild hepatic impairment, and there are insufficient data available for patients with moderate or severe hepatic impairment.

Preparation of PHELINUN solution
Do not use this medicinal product if visible signs of deterioration are observed.
PHELINUN must be prepared at a temperature below 25 °C, reconstituting the lyophilized powder with 10 ml of solvent and shaking vigorously immediately until a clear, particle-free solution is obtained. Use only clear, particle-free solutions.
Unless the concentrate is administered directly into the entry port of a rapid infusion solution, the reconstituted solution must be further diluted before administration with an appropriate volume of 9 mg/ml (0.9%) sodium chloride injection solution to achieve a final concentration between 0.45 and 4.0 mg/ml.
The concentrate and the reconstituted PHELINUN solution have limited stability and must be prepared immediately before use. The maximum time between reconstitution and dilution in 9 mg/ml (0.9%) sodium chloride injection solution and the end of infusion must not exceed 1 hour and 30 minutes.
PHELINUN is incompatible with infusion solutions containing glucose.
Use of 9 mg/ml (0.9%) sodium chloride injection solution only is recommended.
If cloudiness or visible crystallization occurs in reconstituted or diluted solutions, the preparation must be discarded.

Method of administration
PHELINUN is for intravenous use only.
When PHELINUN is administered via peripheral intravenous route, there is a risk of extravasation. In case of extravasation, administration must be immediately stopped and a central venous catheter used instead.
It is recommended to inject PHELINUN slowly as a concentrate (5 mg/ml) into the port of a rapid infusion solution.
When PHELINUN is administered at high doses, with or without transplantation, administration via dilution through a central venous catheter is recommended to avoid extravasation. If slow injection of the concentrate (5 mg/ml) into a rapid infusion solution is not suitable, PHELINUN may alternatively be administered further diluted with 9 mg/ml (0.9%) sodium chloride injection solution as a "slow" infusion in an infusion bag.
When further diluted in an infusion solution, the stability of PHELINUN is reduced and degradation rate increases rapidly with rising temperature.
It is recommended that the infusion be administered at a temperature below 25 °C.

Disposal
Unused solution after 1.5 hours must be discarded according to standard guidelines for handling and disposal of cytotoxic medicinal products.
Unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations regarding cytotoxic drugs.

Package leaflet: Information for the user

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion

melphalan
Please read 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 questions, ask your doctor.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

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

1. What PHELINUN is and what it is used for

PHELINUN contains the active substance called melphalan, which belongs to a group of medicines known as cytotoxic agents (also called chemotherapeutic agents), and works by reducing the number of certain cells.
PHELINUN may be used alone or in combination with other medicines or with total body irradiation for the treatment of:

• various types of bone marrow cancer: multiple myeloma, acute lymphoblastic leukaemia (also known as acute lymphocytic leukaemia, ALL) and acute myeloid leukaemia (AML);
• malignant lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), a cancer affecting certain types of white blood cells called lymphocytes (cells that fight infections);
• neuroblastoma, a type of cancer developing from abnormal nerve cells within the body;
• advanced ovarian cancer;
• advanced breast cancer.

PHELINUN is also used, in combination with other cytotoxic medicines, as a conditioning agent prior to haematopoietic stem cell transplantation for the treatment of blood cancers in adults as well as cancers and non-cancerous blood disorders in the paediatric population.

2. What you should know before being given PHELINUN

If you have any doubts, do not hesitate to ask your doctor for advice.
PHELINUN must not be administered to you

• if you are allergic to melphalan or to any of the other ingredients of this medicine (listed in section 6); if you are pregnant (only regarding treatment prior to haematopoietic stem cell transplantation) or if you are breastfeeding (see section 2 “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
If you are about to undergo treatment with melphalan, close monitoring of your blood will be carried out, as this medicine is a potent cytotoxic agent that causes a significant reduction in blood cells.
Before treatment with melphalan, inform your doctor if any of the following conditions apply to you:

• if you have recently undergone radiotherapy or received anticancer medicines, as these often reduce blood cell levels;
• if you show signs of infection (fever, chills, etc.). During treatment with melphalan, your doctor may prescribe medicines such as antibiotics, antifungals or antivirals to prevent infections. Your doctor may also consider administering blood-derived products (e.g. red blood cells and platelets);
• if you have kidney problems or renal failure (when kidneys do not function adequately). In such cases, the dose of PHELINUN must be reduced;
• if you have ever had a blood clot in your veins (thrombosis). The use of melphalan in combination with lenalidomide and prednisone or thalidomide or dexamethasone may increase the risk of developing blood clots. Your doctor may decide to prescribe medicines to prevent this.

During treatment with melphalan, adequate hydration and forced diuresis (large volume of fluids administered intravenously via infusion) are recommended.
Antimicrobial medicines will be administered to prevent and treat infections.
Antiemetic medicines will be administered to prevent and treat gastrointestinal complications.
Children and adolescents
Children and adolescents may be at higher risk of developing severe respiratory and gastrointestinal complications. Inform your doctor or nurse immediately if you experience any respiratory or gastrointestinal symptoms.
Melphalan must not be used as a conditioning agent prior to haematopoietic stem cell transplantation in adolescents over 12 years of age with acute myeloid leukaemia.
The safety and efficacy of melphalan as a conditioning agent prior to haematopoietic stem cell transplantation in children under 2 years of age for the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia have not been established.

Other medicines and PHELINUN
Inform your doctor or nurse if you are taking or have recently taken any other medicines, including those not requiring a prescription.
In particular, inform your doctor or nurse if you are taking any of the following medicines:

• other cytotoxic medicines (chemotherapy);
• nalidixic acid (an antibiotic used to treat urinary tract infections). In children, this may cause fatal haemorrhagic enterocolitis when administered in combination with melphalan;
• busulfan (used to treat a certain type of cancer). In children, administration of melphalan less than 24 hours after the last oral dose of busulfan has been reported to affect the development of toxicity;
• if you are about to receive or have recently received a vaccination, as some live attenuated vaccines (such as those for polio, measles, mumps and rubella) may cause infection during treatment with melphalan.

Cases of impaired kidney function have been reported when cyclosporine is used to prevent graft-versus-host disease following haematopoietic stem cell transplantation.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before receiving this medicine.
Pregnancy
Haematopoietic stem cell transplantation is contraindicated in pregnant women. For other indications, treatment with melphalan is not recommended during pregnancy because it may cause permanent harm to the foetus.
If you are already pregnant, it is important to consult your doctor before receiving melphalan.
Your doctor will need to evaluate, together with you, the risks and benefits of melphalan treatment for both you and your baby.
Effective contraceptive measures must be used during treatment with melphalan and for 6 months after treatment to avoid pregnancy.
Breastfeeding
It is not known whether melphalan passes into breast milk. Do not breastfeed during treatment with PHELINUN.
Fertility
Melphalan may affect the ovaries or sperm, causing infertility (inability to have a child).
In women, ovulation and consequently the menstrual cycle may cease (amenorrhoea). In men, based on animal studies, absence or low levels of viable sperm may occur. Therefore, men are advised to seek counselling about sperm preservation before treatment.
Male and female contraception
It is recommended that both men and women undergoing treatment with melphalan use effective contraceptive measures during treatment and for 6 months after treatment.

Driving and using machines
This medicine may cause nausea and vomiting, which could impair your ability to drive or operate machinery. This medicine also contains alcohol, which may affect children and adolescents (see section 2 “PHELINUN contains ethanol (alcohol)”).

PHELINUN contains ethanol (alcohol)
This medicine contains 1.6 g of alcohol (ethanol) per vial of solvent, equivalent to 42 mg/ml (0.42% weight/volume). The amount of alcohol in the solvent vial is equivalent to 40 ml of beer or 17 ml of wine.
Adults
The amount of alcohol contained in this medicine is not sufficient to produce adverse effects in adults.
However, the alcohol in this medicine may alter the effect of other medicines.
Consult your doctor or pharmacist if you are taking other medicines.
If you are pregnant or breastfeeding, consult your doctor or pharmacist before using this medicine. See also the information above under “Pregnancy”.
If you are alcohol-dependent, consult your doctor or pharmacist before using this medicine.
Children and adolescents
The alcohol contained in this formulation may affect children and adolescents, including causing drowsiness and behavioural changes. It may also impair concentration and ability to participate in physical activities. If you have epilepsy or liver problems, consult your doctor or pharmacist before using this medicine.
The amount of alcohol in this medicine may alter the effect of other medicines.
Consult your doctor or pharmacist if you are taking other medicines.
If you are pregnant or breastfeeding, consult your doctor or pharmacist before using this medicine. See also the information above under “Pregnancy”.
If you are alcohol-dependent, consult your doctor or pharmacist before using this medicine.

PHELINUN contains propylene glycol
This medicine contains 24.9 g of propylene glycol in each 40 ml of solvent, equivalent to 0.62 g/ml.
If your child is under 5 years of age, consult your doctor or pharmacist before administering this medicine, especially if they are taking other medicines containing propylene glycol or alcohol.
If you are pregnant or breastfeeding, do not take this medicine unless recommended by your doctor. See also the information above under “Pregnancy”.
If you have liver or kidney disease, do not take this medicine unless recommended by your doctor. Your doctor may perform additional monitoring during treatment.
The propylene glycol in this medicine may have effects similar to those of alcoholic beverages and may therefore increase the likelihood of adverse effects.
Use this medicine only if recommended by a doctor. Your doctor may perform additional monitoring during treatment.

PHELINUN contains sodium
This medicine contains 62.52 mg of sodium (the main component of table salt) per vial, equivalent to 3% of the maximum daily recommended sodium intake for an adult.

3. How PHELINUN is administered

PHELINUN will always be administered by a healthcare professional experienced in the use of anticancer medicines or in stem cell transplantation.
Your doctor will calculate the dose of PHELINUN based on your body surface area or body weight, your disease, and your kidney function.
When PHELINUN is used as a treatment prior to haematopoietic stem cell transplantation, it is always administered in combination with other medicines.

Use in adults
The recommended dosage range is between 100 and 200 mg/m² of total body surface area.
The dose may be divided equally over 2 or 3 consecutive days.

Use in the paediatric population
The dosage regimen is as follows: a dose between 100 and 240 mg/m² of total body surface area.
The dose may be divided equally over 2 or 3 consecutive days.

Use in patients with reduced renal function
In general, the dose is lower depending on the severity of the kidney problem.

Administration
PHELINUN is administered by intravenous infusion (drip).
If PHELINUN is accidentally injected outside the vein into the surrounding tissue or leaks out of the vein into the surrounding tissue (extravasation), administration of PHELINUN must be stopped immediately, as it may cause severe tissue damage, typically resulting in sharp pain and burning. If patients are unable to report pain, other signs such as redness and swelling at the injection site should be carefully observed.

If you are given more PHELINUN than you should receive
If you think that you have been given too high a dose or that a dose has been missed, inform your doctor or nurse immediately.

If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor, pharmacist, or nurse immediately if you experience any of the following side effects.

Serious side effects
If you experience any of the following side effects, consult your specialist or go to hospital immediately:

• Graft-versus-host disease following haematopoietic stem cell transplantation (when transplanted cells attack the body, potentially fatal)
• Decrease in circulating blood cells and platelets, which may lead to anaemia (reduction in red blood cells), abnormal bleeding, bruising
• Infection, sometimes severe and potentially fatal
• Gastrointestinal bleeding
• Dysfunction of two or more organ systems, which may cause discomfort and can be potentially fatal
• Disorders of female reproductive function that may cause ovarian dysfunction and premature menopause
• In men: absence of sperm in semen (azoospermia)
• Septic shock
• Progression, relapse, or recurrence of cancer, development of a new cancer
• Leukaemia, myelodysplastic syndrome (a specific type of blood cancer)
• Respiratory disorders: respiratory failure, shortness of breath (acute respiratory distress syndrome), lung inflammation (pneumonia, idiopathic pneumonia syndrome), thickening of lung tissue (interstitial lung disease, pulmonary fibrosis), bleeding in the lungs
• Formation of blood clots in small blood vessels throughout the body, damaging brain, kidneys, and heart
• Bleeding in the brain
• Liver disorders: toxic liver injury, blockage of a hepatic vein
• Kidney damage (acute kidney injury, nephrotic syndrome), reduced kidney function
• Allergic reaction; signs may include hives, swelling (edema), skin rash, loss of consciousness, breathing difficulties, hypotension, heart failure, and death
• Collapse (due to cardiac arrest)
• A condition in which red blood cells are destroyed prematurely, leading to extreme tiredness, shortness of breath, dizziness, and possibly headache or yellowing of the skin or eyes (jaundice)
• Cardiovascular disorders: changes and abnormalities in the heart's ability to pump, causing fluid retention, shortness of breath, and feeling of fatigue (heart failure, cardiomyopathy), and inflammation around the heart (pericardial effusion)
• High blood pressure in the lung arteries (pulmonary hypertension)
• Severe inflammatory and immunological complications (haemophagocytic lymphohistiocytosis)
• Severe skin damage (e.g. lesions, blisters, peeling in severe cases), which may affect the entire body surface and can be potentially fatal (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Bleeding
• Formation of blood clots in a deep vein, particularly in the legs (deep vein thrombosis), and blockage of the pulmonary artery (pulmonary embolism)

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

• Alopecia (hair loss), at high doses

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

• Nausea
• Vomiting
• Diarrhoea
• Inflammation inside and around the mouth (stomatitis)
• Fever, chills
• Absence of menstrual periods (amenorrhoea)
• Alopecia (hair loss), at normal doses

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

• Skin disorders: skin redness with small confluent pustules (maculopapular rash)
• Patients with severe blood disorders may experience a sensation of warmth or tingling

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

• Itching (pruritus)
• Liver problems that may appear in blood tests or cause jaundice (yellowing of the whites of the eyes and skin)

Not known (frequency cannot be estimated from available data)

• Inflammation of the bladder with blood in the urine
• Elevated levels of creatinine in the blood

Other side effects in children and adolescents
Children and adolescents may be more likely to develop severe respiratory and gastrointestinal complications.

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

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store PHELINUN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the carton after "Exp.". The expiry date refers to the last day of that month.
Do not refrigerate.
Keep the vials in the outer cardboard box to protect the medicine from light.
After reconstitution and dilution, the product is stable for 1 hour and 30 minutes at 25 °C. Therefore, the total time from reconstitution and dilution to completion of infusion must not exceed 1 hour and 30 minutes.
From a microbiological standpoint, the product should be used immediately.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What PHELINUN contains

• The active substance is melphalan. One vial of powder contains 200 mg of melphalan (as melphalan hydrochloride). After reconstitution with 40 ml of solvent, the final concentration of the solution is 5 mg/ml of melphalan.
• The other components are:
  Powder: hydrochloric acid (E507) and povidone (E1201)
  Solvent: water for injections, propylene glycol (E1520), ethanol, and sodium citrate (E331) (see section 2).

Description of the appearance of PHELINUN and contents of the pack
PHELINUN is a powder and solvent for concentrate for solution for infusion.
The powder is supplied in a clear glass vial containing a white to pale yellow powder or agglomerate. The solvent is a clear, colourless solution contained in a clear glass vial.
Each pack of PHELINUN contains: one vial with 200 mg of powder (melphalan) and one vial with 40 ml of solvent.

Marketing Authorization Holder
ADIENNE S.r.l. S.U.
Via Galileo Galilei, 19
20867 Caponago (MB)
Italy
Tel: +39 0240700445
E-mail: [email protected]

Manufacturer
NERPHARMA S.R.L.
Viale Pasteur, 10
20014 Nerviano (MI)
Italy
Tel: +39 0331 581111

Marketing Authorization Holder and Manufacturer
ADIENNE S.r.l. S.U.
Via Galileo Galilei, 19
20867 Caponago (MB)
Italy
Tel: +39-02 40700445
[email protected]

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu

The following information is intended exclusively for healthcare professionals:

PHELINUN 200 mg powder and solvent for concentrate for solution for infusion
As with any high-dose chemotherapy, preparation and handling of this product require specific precautions to ensure protection of both healthcare personnel and the surrounding environment, while also considering the safety requirements for the patient.
In addition to standard precautions aimed at maintaining sterility of injectable preparations, the following measures are necessary:

• Wear long-sleeved clothing with tight cuffs to prevent splashing of solution onto the skin;
• Wear a disposable surgical mask and safety goggles;
• Wear disposable gloves after washing hands under aseptic conditions;
• Prepare the solution in a designated area;
• Interrupt the infusion in case of extravasation;
• Dispose of materials used in the preparation of the solution (syringes, gauze, drapes, vial) in appropriate containers;
• Destroy contaminated waste;
• Handle excreta and vomit with caution.

If PHELINUN comes into accidental contact with the skin, the affected areas must be washed immediately and thoroughly with soap and water.
In case of accidental contact with eyes or mucous membranes, rinse thoroughly with abundant water.
Avoid inhalation of the product.
Pregnant women must not handle cytotoxic medicinal products.

Dosage

Adults
Multiple myeloma, malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma), acute lymphoblastic and acute myeloblastic leukemia (ALL and AML), ovarian cancer, and high-dose breast adenocarcinoma
The dosage regimen is as follows: a dose ranging between 100 and 200 mg/m² of total body surface area (approximately 2.5–5.0 mg/kg body weight). The dose may be equally divided over 2 or 3 consecutive days. An autologous hematopoietic stem cell transplant is required following doses exceeding 140 mg/m² of total body surface area.

Hematological malignancies prior to allogeneic hematopoietic stem cell transplant
The recommended dose is 140 mg/m² as a single daily infusion or 70 mg/m² once daily for two consecutive days.

Paediatric population
Acute lymphoblastic and acute myeloblastic leukemia at high doses
The dosage regimen is as follows: a dose ranging between 100 and 200 mg/m² of total body surface area (approximately 2.5–5.0 mg/kg body weight). The dose may be equally divided over 2 or 3 consecutive days. An autologous hematopoietic stem cell transplant is required following doses exceeding 140 mg/m² of total body surface area.

Paediatric neuroblastoma
The recommended dose to consolidate a response achieved with conventional therapy is a single dose ranging between 100 mg/m² and 240 mg/m² of total body surface area (sometimes equally divided over 3 consecutive days), together with an autologous hematopoietic stem cell transplant. The infusion may be used alone or in combination with radiotherapy and/or other cytotoxic medicinal products.

Haematological disorders prior to allogeneic haematopoietic stem cell transplant
The recommended dose is as follows:

• Malignant haematological disorders: 140 mg/m² as a single daily infusion;
• Non-malignant haematological disorders: 140 mg/m² as a single daily infusion or 70 mg/m² once daily for two consecutive days.

Thromboembolic complications
Antithrombotic prophylaxis should be administered for at least the first 5 months of treatment, particularly in patients at higher risk of thrombosis. The decision to implement antithrombotic prophylactic measures should be made after a thorough assessment of the individual patient's underlying risks (see sections 4.4 and 4.8).
It is recommended to ensure adequate hydration and forced diuresis in patients, as well as the prophylactic administration of anti-infective agents (against bacteria, fungi, or viruses) (see section 4.4).
Pre-treatment with cyclophosphamide appears to reduce the severity of gastrointestinal damage induced by high-dose PHELINUN; consult the literature for details (see section 4.8).
Prophylactic measures, such as administration of anti-infective agents, may be beneficial (see section 4.8).
The occurrence of graft-versus-host disease (GvHD) may be prevented by using immunosuppressive therapy as prophylaxis following hematopoietic stem cell transplantation (see section 4.8).

Special populations
Elderly
There are no specific dosage recommendations for administration of PHELINUN in elderly patients.
However, conventional doses of melphalan are frequently administered to elderly patients.
Experience with high-dose melphalan in elderly patients is limited. Therefore, adequate performance status and organ function should be carefully considered before administering high-dose melphalan to elderly patients.

Renal impairment
Dosage adjustment is required in patients with renal impairment (see section 4.4).
Melphalan clearance, although variable, may be reduced in patients with impaired renal function.
High-dose melphalan combined with hematopoietic stem cell rescue has been successfully used in dialysis-dependent patients with end-stage renal failure. As a general guideline, for high-dose melphalan treatment without hematopoietic stem cell transplant in patients with moderate renal impairment (creatinine clearance 30–50 ml/min), a 50% dose reduction is typically applied. High-dose melphalan (doses exceeding 140 mg/m²) without hematopoietic stem cell transplant must not be used in patients with more severe renal impairment.
For high-dose intravenous melphalan (100–240 mg/m² of total body surface area), the need for dose reduction depends on the degree of renal impairment, whether hematopoietic stem cells are to be reinfused, and therapeutic necessity. Melphalan injection must be administered with hematopoietic stem cell rescue at doses exceeding 140 mg/m².

Hepatic impairment
No dosage adjustment is required in patients with mild hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment.

Preparation of PHELINUN solution
Do not use this medicinal product if visible signs of deterioration are observed.
PHELINUN must be prepared at a temperature below 25 °C, reconstituting the lyophilized powder with 40 ml of solvent and shaking vigorously immediately until a clear, particle-free solution is obtained. Use only clear solutions free from visible particles.
Unless the concentrate is administered directly into the inlet of a rapid infusion solution via an injection port, the reconstituted solution must be further diluted prior to administration with an appropriate volume of 9 mg/ml (0.9%) sodium chloride injection solution to achieve a final concentration between 0.45 and 4.0 mg/ml.
The concentrate and reconstituted PHELINUN solution have limited stability and must be prepared immediately before use. The maximum time between reconstitution, dilution with 9 mg/ml (0.9%) sodium chloride injection solution, and completion of infusion must not exceed 1 hour and 30 minutes.
PHELINUN is incompatible with infusion solutions containing glucose.
Use of 9 mg/ml (0.9%) sodium chloride injection solution is recommended exclusively.
If cloudiness or visible crystallization occurs in reconstituted or diluted solutions, the preparation must be discarded.

Method of administration
PHELINUN is for intravenous use only.
When PHELINUN is administered via peripheral intravenous route, there is a risk of extravasation. In case of extravasation, administration must be immediately stopped and a central venous catheter should be used.
It is recommended to inject PHELINUN slowly as a concentrate (5 mg/ml) into the injection port of a rapid infusion solution.
When PHELINUN is administered at high doses, with or without transplant, administration via dilution through a central venous catheter is recommended to avoid extravasation. If slow injection of the concentrate (5 mg/ml) into a rapid infusion solution is not suitable, PHELINUN may be further diluted with 9 mg/ml (0.9%) sodium chloride injection solution and administered as a "slow" infusion in an infusion bag.
When further diluted in an infusion solution, the stability of PHELINUN is reduced and degradation rate increases rapidly with rising temperature.
It is recommended that the infusion be maintained at a temperature below 25 °C.

Disposal
Any unused solution after 1.5 hours must be discarded according to standard guidelines for handling and disposal of cytotoxic medicinal products.
Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations governing cytotoxic medicinal products.