AMBISOME LIPOSOMAL 50 mg POWDER FOR DISPERSION FOR INFUSION

Introduction

Prospective:Information for the user

AmBisome liposomal50 mg powder for dispersion for infusion

AmphotericinB (in liposomes)

Read the entire prospectus carefully before this medication is administered to you, as it contains important information for you.

• Keep this prospectus, as you may need to read it again.
• If you have any doubts, consult your doctor.
• If you experience side effects, consult your doctor, even if they are side effects not listed in this prospectus. See section 4.

Contents of the prospectus:

1. What AmBisome liposomal is and what it is used for
2. What you need to know before starting to use AmBisome liposomal
3. How to use AmBisome liposomal
4. Possible side effects
5. Storage of AmBisome liposomal

Contents of the package and additional information

1. What AmBisome liposomal is and what it is used for

Amphotericin B is an antifungal, used for the treatment of serious infections caused by fungi. This medication is indicated for:

• Treatment of serious systemic infections caused by fungi.

• Treatment of infections suspected to be caused by fungi in patients with severe neutropenia (patients with a reduced number of a type of white blood cells called "neutrophils"), as a consequence of blood diseases or the use of cytotoxic or immunosuppressive drugs.

• Treatment of visceral leishmaniasis, a disease caused by a parasite.

2. What you need to know before starting to use AmBisome liposomal

Do not use AmBisome liposomal

• If you are allergic (hypersensitive) to amphotericin B or to any of the other components of this medication included in section 6.

Warnings and precautions

Consult your doctor before starting to use this medication.

• -If you have previously experienced a severe anaphylactoidor anaphylactic reactionto this medication (a severe allergic reaction, potentially life-threatening, with symptoms of flushing, itching, dizziness, swelling of the face, mouth, tongue, and respiratory tract, often sufficient to cause difficulty breathing).

If this occurs, your doctor will stop the treatment

• If you experience other reactions that are thought to be related to the infusion. If this occurs, your doctor may reduce the infusion rate so that you receive this medication over a longer period of time (approximately 2 hours). Your doctor may also give you medications, such as diphenhydramine (an antihistamine), paracetamol, pethidine (a pain reliever), and/or hydrocortisone (an anti-inflammatory medication that acts by reducing the response of your immune system), to prevent or treat infusion-related reactions.
• If you are taking other medications that may cause kidney damage, see the section Other medications and AmBisome. AmBisome may damage the kidneys. Your doctor or nurse will take blood samples to measure your creatinine (a chemical substance in the blood that reflects kidney function) and electrolyte levels (especially potassium and magnesium) before and during treatment with AmBisome, as both may be abnormal if you have changes in kidney function. This is especially important if you have previously suffered kidney damage or are taking other medications that may affect kidney function. Blood samples will also be analyzed to detect changes in liver function and the body's ability to produce new blood cells and platelets. If blood tests show a change in kidney function or other significant changes, your doctor may administer a lower dose of AmBisome or interrupt treatment.
• If blood tests show that your potassium levels are low. If this happens, your doctor may prescribe a potassium supplement for you to take while being treated with AmBisome.
• If blood tests show that your potassium levels are high, you may experience irregular heartbeats, sometimes severe.
• If the results of your blood tests show a change in kidney function or other significant changes. If this occurs, your doctor may give you a lower dose of the medication or suspend treatment.
  • If you are receiving or have recently received a white blood cell transfusion. As sudden and severe lung problems can occur, your doctor will advise you to separate the infusions as much as possible to reduce the risk of lung problems and will monitor lung function.
  • If you are receiving hemodialysis or filtration for kidney failure. Your doctor may start treatment with this medication once the procedure has been completed.
  • Interference with phosphorus values in blood tests when using a specific system, called the PHOSm assay, which may result in false readings showing increased phosphate levels in the blood.

If your test results show high phosphate levels, it may be necessary to perform additional tests using a different system to confirm the results.

• If you are diabetic. This medication contains approximately 900 milligrams of sucrose (sugar) per vial.

Other medications and AmBisome liposomal. Use of other medications

Tell your doctor if you are using or have recently used or may need to use any other medication.

The following medications interact with amphotericin B and may interact with this medication.

• Medications that may be harmful to the kidneys,including:

• Immunosuppressive drugs (medications that reduce the activity of the body's natural defenses) such as cyclosporine.
• Antibiotics (medications used to treat bacterial infections) from the group known as aminoglycosides, which include gentamicin, neomycin, and streptomycin.
• Pentamidine, a medication used to treat pneumonia in patients with AIDS and leishmaniasis.

These medications may damage the kidneys, and AmBisome liposomal may worsen the damage caused by these medications to the kidneys. If you are taking medications that may damage the kidneys, your doctor or nurse will periodically take blood samples to analyze changes in kidney function.

• Medications that may reduce your potassium levels,including:

• Corticosteroids (anti-inflammatory medications that act by reducing the response of your immune system) and corticotropin (ACTH), used to control the rate of production of the body's natural corticoids in response to stress situations.
• Diuretics (medications that increase the volume of urine produced), such as furosemide.
• Digitalis glycosides, medications produced from the digitalis plant, used to treat heart failure. This medication may decrease potassium levels in the blood, worsening the side effects of digitalis (changes in heart rhythm).
• Muscle relaxants (e.g., tubocurarine). This medication may increase the muscle relaxant effect.

• Other medications

• Antifungal medications (medications used to treat fungal infections), such as flucytosine. This medication may worsen the side effects of flucytosine (changes in the body's ability to produce new blood cells, reflected in blood tests).
• Antineoplastic medications (anticancer medications), such as methotrexate, doxorubicin, carmustine, and cyclophosphamide. The use of these medications during the infusion of this medication may cause kidney damage, wheezing, or breathing difficulties and low blood pressure.
• White blood cell transfusions. Sudden and severe lung problems have been described in patients treated with amphotericin B. See also, Be careful with AmBisome liposomal

Pregnancy and breastfeeding

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

The safety of this medication in pregnant women is unknown. If you are pregnant, your doctor will only prescribe this medication if it is believed that the benefits of treatment outweigh the potential risks to you and your baby.

It is unknown whether this medication passes into breast milk. While receiving this medication, the potential risk to the child and the benefits of breastfeeding for the child and the benefits of treatment with AmBisome liposomal for the mother should be considered.

Driving and using machines

Some of the side effects of this medication may affect your ability to drive vehicles or use machines safely (see section 4 on possible side effects).

AmBisome liposomal contains sodium

This medication contains less than 23 mg (1 mmol) of sodium per dose, so it is considered essentially "sodium-free".

3. How to use AmBisome liposomal

Your doctor or nurse will administer this medication to you personally.

If you are a patient undergoing dialysis, your doctor should start administering this medication when each dialysis session has ended (see the section Be careful with AmBisome liposomal)

Your doctor will indicate the dose of this medication that you should receive, based on your specific needs. It is administered by intravenous infusion over a period of 30 to 60 minutes, once a day.

The recommended dose of AmBisome liposomal is:

• 1-3 mg/kg of body weight per day, for the treatment of confirmed or suspected fungal infections. This dose may be increased to 5 mg/kg of body weight per day if the infection is very severe.
• For mucormycosis, the initial dose is generally 5 mg/kg of body weight per day. Your doctor will assess the dose and the duration of treatment will be determined individually. Treatment should continue until the signs and symptoms of the infection have disappeared.
• 1 to 1.5 mg/kg of body weight per day, for 21 days or 3 mg/kg of body weight per day for 10 days, for the treatment of visceral leishmaniasis.

If you have visceral leishmaniasis, you will receive this medication for 10 or 21 days. If the infection recurs, you may need additional treatment for a longer or shorter period to control the infection (also known as maintenance therapy).

If you use more AmBisome liposomal than you should

Tell your doctor or nurse immediately if you think you have been given too much AmBisome liposomal.

Tell your doctor or nurse immediately if you experience any of the side effects listed in section 4 of this prospectus, as some of them may occur if you receive too much AmBisome liposomal. If you have received too much AmBisome liposomal, your doctor will closely monitor you and, if necessary, provide treatment for the symptoms of overdose.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, telephone (91) 5 62 04 20, indicating the medication and the amount ingested

If you forget to use AmBisome liposomal

Your doctor will decide whether you need to receive an additional dose of this medication if a dose has been missed.

If you interrupt treatment with AmBisome liposomal

Your doctor will indicate the duration of your treatment with this medication based on your specific needs. Do not interrupt treatment with this medication, even if you feel better, before your doctor makes that decision, as your illness may continue if you do not receive the complete treatment.

4. Possible side effects

Like all medications, AmBisome liposomal may cause side effects, although not everyone will experience them.

The most frequent infusion-related reactions that can be expected are fever, chills, and rigors. Less frequent infusion-related reactions may include chest tightness, chest pain, shortness of breath, difficulty breathing (possibly with wheezing), flushing, faster than normal heart rate, low blood pressure, and musculoskeletal pain (described as joint pain, back pain, or bone pain). All of these disappear soon after the infusion is stopped. These reactions do not have to occur with subsequent infusions of AmBisome liposomal or if the infusion rate is reduced (over 2 hours). Your doctor may administer other medications to prevent or treat infusion-related reactions or to treat symptoms if they appear. If you experience a severe infusion-related reaction, your doctor will stop the infusion of AmBisome liposomal and you should not receive this treatment in the future.

The following side effects have occurred during treatment with AmBisome liposomal:

Very common: may affect more than 1 in 10 people:

• Feeling of fatigue or confusion or weakness or muscle cramps caused by low potassium levels in the blood.
• Feeling of dizziness or nausea.
• Fever, chills, or rigors, stiffness.

Common: may affect up to 1 in 10 people:

• Feeling of fatigue or confusion or weakness or muscle cramps caused by low magnesium, calcium, or sodium levels in the blood.
• Increased blood sugar levels.
• Headache.
• Faster than normal heart rate.
• Vasodilation, low blood pressure, and flushing (redness of the skin).
• Shortness of breath.
• Diarrhea, abdominal pain.
• Abnormal liver or kidney function test results that are observed in blood or urine tests.
• Rash
• Chest or back pain.
• High potassium levels in the blood.

Uncommon: may affect up to 1 in 100 people:

• Bleeding into the skin, bruising without a known cause, or prolonged bleeding after an injury.
• Anaphylactoid reaction (for information on anaphylactoid reactions, see section 2 of this prospectus).
• Seizures (attacks or crises).
• Difficulty breathing, possibly with wheezing (whistling).

Additionally, the following side effects have been observed during treatment with AmBisome liposomal, but it is not known how frequently they occur.

• Anemia (decrease in the number of red blood cells in the blood, with symptoms of excessive fatigue, shortness of breath after light activity, and paleness).
• Anaphylactic and hypersensitivity reactions (for information on anaphylactic reactions, see section 2 of this prospectus).
• Heart attacks (myocardial infarction) and changes in normal heart rhythm.
• Kidney failure and decreased kidney function.
• Severe swelling of the skin around the lips, eyes, or tongue.
• Muscle rupture
• Bone pain and joint pain.

If you consider that any of the side effects you are experiencing is serious or if you experience any side effect not mentioned in this prospectus, inform your doctor.

Reporting side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es

By reporting side effects, you can contribute to providing more information on the safety of this medication.

5. Storage of AmBisome liposomal

Keep this medicine out of the sight and reach of children

Do not use this medicine after the expiration date stated on the packaging after CAD. The expiration date refers to the last day of the month

Do not store above 25°C.

Any reconstituted or diluted AmBisome liposomal solution not used immediately should be discarded.

Validity period of AmBisome liposomal before opening the vial

3 years.

Validity period of AmBisome liposomal after opening the vial

The following physical and chemical stability data have been demonstrated:

• Physical and chemical stability after reconstitution with water for injectable preparations:

Glass vials for 24 hours at 25±2°C exposed to ambient light

Glass vials and polypropylene syringes for up to 7 days at 2-8°C. Do not freeze.

• Physical and chemical stability after dilution with glucose:

Infusion bags: See Table for recommendations

From a microbiological point of view, since AmBisome liposomal does not contain any bacteriostatic agent, the reconstituted or diluted product should be used immediately.

If not used immediately, the storage times and conditions before administration are the responsibility of the user and should not normally exceed 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. Do not freeze.

6. Package contents and additional information

Composition of AmBisome liposomal

• The active ingredient is amphotericin B (in liposomes). Each vial contains 50 mg of amphotericin B (in liposomes)
• The other components are: liposome components (hydrogenated soy phosphatidylcholine, cholesterol, distearoyl phosphatidylglycerol, alpha-tocopherol), the other components: sucrose, disodium succinate hexahydrate, sodium hydroxide, and hydrochloric acid.

Appearance of the product and package contents

AmBisome liposomal is a sterile, lyophilized, yellow powder for dispersion for infusion. It is presented in single-dose glass vials. Each vial contains 50 mg of the active ingredient amphotericin B. The closure consists of rubber stoppers sealed with an aluminum ring, provided with a disposable plastic cap. Each cardboard package contains 10 vials and 10 5-micron filters.

Marketing authorization holder and manufacturer

Marketing authorization holder

Gilead Sciences S.L.

Via de los Poblados, 3 ef 7/8 plta 6ª - Pque

Empresarial Cristalia,

(Madrid) - 28033 - Spain

Manufacturer

GILEAD SCIENCES CORK LIMITED

IDA Business and Technology Park (Carrigtohill,

Co. Cork) - - - Ireland

This prospectus was approved in April 2024

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

This information is intended solely for healthcare professionals: INSTRUCTIONS FOR USE/MANIPULATION

READ THIS SECTION CAREFULLY BEFORE STARTING RECONSTITUTION

AmBisome liposomal should not be administered if the presence of particles is detected in the solution for the product's infusion.

AmBisome liposomal is NOT physically compatible with saline solutions.

DO NOT mix AmBisome liposomal with other drugs or electrolytes.

AmBisome liposomal is not interchangeable with other medicines containing amphotericin.

AmBisome liposomal should be reconstituted using Sterile Water for injectable preparations (without a bacteriostatic agent) and diluted in a Glucose solution (5%, 10%, or 20%) exclusively for infusion.

The use of any solution other than the recommended ones, or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the solution, may cause the precipitation of AmBisome liposomal.

AmBisome liposomal is NOT compatible with saline solutions and cannot be reconstituted or diluted with saline solutions, or administered through an intravenous line that has been previously used for saline solutions, unless it is first washed with a glucose solution (5%, 10%, or 20%) for infusion. If this is not feasible, AmBisome liposomal should be administered through a different route.

Aseptic technique will be strictly followed in all manipulations, since AmBisome liposomal does not contain any bacteriostatic or preservative agent, nor do the materials specified for reconstitution and dilution.

The AmBisome liposomal vials, which contain 50 mg of amphotericin, are prepared as follows:

1.- Add 12 ml of Sterile Water for injectable preparations to each vial of AmBisome liposomal, to obtain a preparation containing 4 mg/ml of amphotericin B.

2.- IMMEDIATELY after adding the sterile water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome liposomal. After reconstitution, the concentrate is a translucent yellow dispersion. Do not use if any precipitation of foreign matter is observed..

3.- Calculate the amount of reconstituted AmBisome liposomal (4 mg/ml) for subsequent dilution (see the following table).

The infusion dispersion is obtained by diluting the reconstituted AmBisome liposomal with a volume of between one (1) and nineteen (19) parts of a Glucose solution (5%, 10%, or 20%) for infusion, to obtain a final concentration in the recommended range of 2 mg/ml to 0.2 mg/ml of amphotericin as AmBisome liposomal (see the following table).

4.- Withdraw the calculated volume of reconstituted AmBisome liposomal in a sterile syringe. Using the provided 5-micron filter, instill the AmBisome liposomal preparation into a sterile container with the correct amount of Glucose solution (5%, 10%, or 20%) for infusion.

For the intravenous infusion of AmBisome liposomal, an in-line membrane filter can be used. However, the average pore diameter of the filter should not be less than 1 micron.

Example of preparation of the infusion dispersion of AmBisome liposomal at a dose of 3 mg/kg/day in 5% glucose solution for infusion.

*Each vial of AmBisome liposomal (50 mg) is reconstituted with 12 ml of Water for injectable preparations to provide a concentration of 4 mg/ml of amphotericin B.

Any reconstituted or diluted AmBisome liposomal solution not used immediately should be discarded (never to be stored for reuse).

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