Prospect: information for the user

ZOLSKETIL pegylated liposomal 2mg/ml concentrated solution for infusion

hydrochloride of doxorubicin

Read this prospect carefully before starting to use the medicine, because it contains important information for you.

• Keep this prospect, as you may have to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed only to you and should not be given to other people even if they have the same symptoms as you, as it may harm them..
• If you experience adverse effects, consult your doctor or pharmacist, even if they do not appear in this prospect. See section 4.

ZOLSKETIL pegylated liposomal is an antitumoral agent.

ZOLSKETIL pegylated liposomal is used to treat breast cancer in patients at risk of cardiac problems. ZOLSKETIL pegylated liposomal is also used to treat ovarian cancer. It is used to kill cancer cells, reduce tumor size, slow tumor growth, and increase survival.

ZOLSKETIL pegylated liposomal is also used in combination with another medication, bortezomib, for the treatment of multiple myeloma (a blood cancer) in patients who have received at least one previous treatment.

ZOLSKETIL pegylated liposomal is also used to produce an improvement in Kaposi's sarcoma, including flattening, thinning, and even reduction of cancer. It may also improve and even eliminate other symptoms of Kaposi's sarcoma, such as swelling around the tumor.

ZOLSKETIL pegylated liposomal contains a medication capable of interacting with cells, thereby selectively killing those affected by cancer. Hydrochloride of doxorubicin in ZOLSKETIL pegylated liposomal is enclosed in tiny spheres called pegylated liposomes that facilitate the release of the medication from the bloodstream into the cancerous tissue before normal and healthy tissue.

No use ZOLSKETIL pegylated liposomal

• If you are allergic to hydrochloride doxorubicin, peanuts, or soy, or to any of the components of this medication (listed in section 6).

Warnings and Precautions

Inform your doctor if you experience the following:

• If you are receiving treatment for heart or liver disease;
• If you are diabetic, as ZOLSKETIL pegylated liposomal contains sugar and may require adjustment of your diabetes treatment;
• If you have Kaposi's sarcoma and have had your spleen removed;
• If you notice ulcers, discoloration, or any discomfort in your mouth.
• If your bone marrow is not producing enough blood cells
• If you have cancer where your bone marrow produces abnormal blood cells
• If you experience painful skin eruptions with macular redness
• If there are leaks of medication or vesicants from the vein into the surrounding tissue
• If you have hand-foot syndrome (redness, swelling, and blisters (fluid accumulation between the upper levels of the skin) on the palms of your hands and the soles of your feet)

Strategies for preventing and treating hand-foot syndrome include:

• Soaking your hands and/or feet in cold water when possible (e.g., while watching TV, reading, or listening to the radio);
• Keeping your hands and feet uncovered (without gloves, socks, etc.);
• Staying in cool places;
• Taking cold water baths when it is hot;
• Avoiding strenuous exercise that may cause trauma to your feet (e.g., jogging);
• Avoiding exposure of your skin to very hot water (e.g., hot tubs, saunas);
• Avoiding tight-fitting shoes or high-heeled shoes.

Piridoxina (Vitamin B6):

• Vitamin B6 is available over-the-counter;
• Take 50-150 mg per day starting when the first signs of redness or tingling appear.

Children and Adolescents

ZOLSKETIL pegylated liposomal should not be used in children and adolescents, as its effects on them are unknown.

Use of ZOLSKETIL pegylated liposomal with other medications

Inform your doctor or pharmacist

• If you are using or have recently used any other medication, including those obtained without a prescription;
• About other cancer treatments you are receiving or have received, as you should exercise special caution with treatments that reduce the number of white blood cells, as they may cause a further reduction in white blood cell count. If you are unsure about the treatments you have received or the diseases you have had, discuss it with your doctor.

Pregnancy and Breastfeeding

Consult your doctor or pharmacist before using any medication.

Since the active ingredient hydrochloride doxorubicin in ZOLSKETIL pegylated liposomal may cause birth defects, it is essential to contact your doctor if you believe you are pregnant.

Women should avoid becoming pregnant and use contraceptive methods while undergoing treatment with ZOLSKETIL pegylated liposomal and for eight months after completing treatment. To prevent pregnancy in their partners, men should use contraceptive methods during and for six months after treatment with ZOLSKETIL pegylated liposomal.

Since hydrochloride doxorubicin may be harmful to infants, women should discontinue breastfeeding before starting treatment with ZOLSKETIL pegylated liposomal. Health experts recommend that HIV-infected women not breastfeed their children under any circumstances to prevent HIV transmission.

Driving and Operating Machines

Do not drive or operate tools or machines if you feel tired or drowsy as a result of treatment with ZOLSKETIL pegylated liposomal.

ZOLSKETIL pegylated liposomal contains soy oil and sodium

ZOLSKETIL pegylated liposomal contains soy oil. Do not use this medication if you are allergic to peanuts or soy.

ZOLSKETIL pegylated liposomal contains less than 1 mmol of sodium (23 mg) per dose; this is essentially "sodium-free".

ZOLSKETIL pegylated liposomal is a formulation with specific characteristics. Therefore, it should not be exchanged with other medications that also contain hydrochloride doxorubicin.

How much ZOLSKETIL pegylated liposomal is administered

If you are being treated for breast or ovarian cancer, you will be administered ZOLSKETIL pegylated liposomal at a dose of 50 mg per square meter of your body surface (obtained from your height and weight). The dose is repeated every 4 weeks as long as the disease does not progress and you can tolerate the treatment.

If you are being treated for multiple myeloma, and you have received at least one previous treatment, you will be administered ZOLSKETIL pegylated liposomal at a dose of 30 mg per square meter of your body surface (based on your height and weight) in a 1-hour intravenous infusion on day 4 of the 3-week regimen of bortezomib, and immediately after the bortezomib infusion. The dose will be repeated as long as you respond satisfactorily and tolerate the treatment.

If you are being treated for Kaposi's sarcoma, you will be administered ZOLSKETIL pegylated liposomal at a dose of 20 mg per square meter of your body surface (obtained from your height and weight). The dose is repeated every 2 to 3 weeks for 2 to 3 months, and then as frequently as needed to maintain the improvement of your condition.

How ZOLSKETIL pegylated liposomal is administered

Your doctor will administer ZOLSKETIL pegylated liposomal through a drip (infusion) in a vein. Depending on the dose and indication, this may take from 30 minutes to over an hour (that is, 90 minutes).

If you use more ZOLSKETIL pegylated liposomal than you should

Acute overdosing worsens adverse effects such as mouth ulcers or decreases the number of white blood cells and platelets in the blood. Treatment will include the administration of antibiotics, platelet transfusions, use of factors that stimulate white blood cell production, and symptomatic treatment of mouth ulcers.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

During the infusion of ZOLSKETIL pegylated liposomal, the following reactions may occur:

• severe allergic reaction that may include swelling of the face, lips, mouth, tongue, or throat; difficulty swallowing or breathing; pruritic exanthema (urticaria)
• inflammation and narrowing of the pulmonary airways, causing cough, wheezing, and difficulty breathing (asthma)
• redness, sweating, chills, or fever
• chest pain or discomfort
• back pain
• increase or decrease in blood pressure
• rapid heart rate
• crisis (seizures)

A leak of the injection fluid from the veins into the tissue under the skin may occur. If the drip stings or hurts while you are receiving a dose of ZOLSKETIL pegylated liposomal, inform your doctor immediately.

Inform your doctor immediately if you observe any of the following severe side effects:

• has fever, feels tired, or presents signs of bruises or bleeding (very common)
• redness, swelling, peeling, or pain on palpation, mainly in hands or feet (hand-foot syndrome). These effects have been seen very frequently and, sometimes, are severe. In severe cases, these effects may interfere with certain daily activities and may last up to 4 weeks or more before resolving completely. The doctor may delay the start and/or reduce the dose of the next treatment (see Strategies for preventing and treating hand-foot syndrome)
• mouth sores, severe diarrhea, or vomiting or nausea (very common)
• infections (common), including pulmonary infections (pneumonia) or infections that may affect your vision
• difficulty breathing (common)
• severe stomach pain (common)
• severe weakness (common)
• severe allergic reaction that may include swelling of the face, lips, mouth, tongue, or throat; difficulty swallowing or breathing; pruritic exanthema (urticaria) (rare)
• cardiac arrest (the heart stops beating); heart failure, in which the heart does not pump enough blood to the rest of the body, which may cause difficulty breathing and may cause swelling of the legs (rare)
• formation of clots in the blood that reaches the lungs, causing chest pain and difficulty breathing (rare)
• swelling, heat, or pain on palpation in some area of the leg, sometimes with pain that worsens when standing or walking (rare)
• severe or potentially fatal rash with blisters and peeling, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome) or on most of the body (toxic epidermal necrolysis) (rare)

Other side effects

Between infusions, the following may occur:

Very common side effects(may affect more than 1 in 10 patients)

• decrease in the number of white blood cells, which may increase the risk of infection. In rare cases, the decrease in white blood cells may lead to a severe infection. Anemia (decrease in red blood cells) may cause fatigue, and a decrease in platelets in the blood may increase the risk of bleeding. Due to possible changes in your blood cells, you will be subject to regular blood tests
• loss of appetite
• constipation
• skin eruptions, including redness of the skin, allergic skin eruption, hives, or skin blisters
• hair loss
• pain, including muscle pain and chest pain, joint pain, arm pain, or leg pain
• feeling extremely tired

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

• infections, including severe infection of the whole body (sepsis), pulmonary infections, herpes virus infections (herpes), a type of bacterial infection (infection by mycobacterium avium complex), urinary tract infections, fungal infections (including cold sores and oral cold sores in the mouth), follicular infections, throat or nose infections, or respiratory tract infections (cold)
• low number of a type of white blood cell (neutrophils), with fever
• severe weight loss and muscle weakness, dehydration, low levels of potassium, sodium, or calcium in the blood
• feeling confused, anxious, depressed, or having difficulty sleeping
• nervous system damage that may cause tingling, numbness, pain, or loss of sensation, pain in nerves, strange sensation in the skin (such as tingling or prickling), decreased sensitivity, especially in the skin
• change in sense of taste, headache, feeling extremely sleepy with little energy, feeling dizzy
• inflammation of the eyes (conjunctivitis)
• rapid heart rate
• increase or decrease in blood pressure, facial redness
• difficulty breathing that may occur after physical activity, nasal bleeding, cough
• inflammation of the gastric mucosa or esophagus, ulcers (sores) in the mouth, indigestion, difficulty swallowing, pain in the mouth, dry mouth
• skin problems, including dry or scaly skin, erythema, blisters, or ulcers (sores) in the skin, itching, dark spots on the skin
• excessive sweating
• muscle spasms or pain
• pain affecting muscles, bones, or back
• pain while urinating
• allergic reaction to the infusion of the medicine, illness similar to the flu, chills, inflammation of the mucosa of different cavities and conductors of the body, such as nose, mouth, or trachea, feeling weak, feeling generally unwell, swelling caused by fluid retention, feeling swelling of hands, ankles, or feet
• weight loss

When ZOLSKETIL pegylated liposomal is used as the only medicine, it is less likely that some of these side effects will occur, and some of them have never occurred.

Rare side effects(may affect up to 1 in 100 patients)

• herpes simplex virus infections (herpes labial or herpes genital), fungal infections
• low number of all types of blood cells, increase in the number of ‘platelets’ (cells that help blood to clot)
• allergic reaction
• high level of potassium in the blood, low level of magnesium in the blood
• nerve damage affecting more than one area of the body
• crisis (seizures), fainting
• unpleasant or painful sensation, especially to the touch, drowsiness
• blurred vision, watery eyes
• feeling of rapid or irregular heartbeat (palpitations), heart muscle disease, cardiac damage
• damage to tissues (necrosis) at the injection site, inflammation of the veins causing swelling and pain, feeling dizzy when sitting or standing
• chest pain
• flatulence, inflamed gums (gingivitis)
• skin problems or eruptions, including dry or scaly skin, allergic eruption, ulcers (sores) or blisters in the skin, skin discoloration, change in natural skin color (pigmentation), small red or purple spots caused by bleeding under the skin, nail problems, acne
• muscle weakness
• breast pain
• irritation or pain at the injection site
• swollen face, elevated body temperature
• symptoms (such as inflammation, redness, or pain) in areas of the body that have been previously treated with radiation or that have been damaged as a result of an intravenous injection of chemotherapy

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

• infection that occurs in people with a weakened immune system
• low number of blood cells generated in the bone marrow
• inflammation of the retina, which may cause changes in vision or blindness
• abnormal heart rhythm, abnormal ECG tracing that may occur with low heart rate, heart problem affecting heart rate and rhythm, blue discoloration of the skin and mucous membranes caused by low oxygen levels in the blood
• dilation of blood vessels
• feeling of throat constriction
• sores and swelling in the tongue, ulcers (sores) in the lips
• skin eruption with blisters filled with fluid
• vaginal infection, scrotal redness
• problems with the mucous membranes of different cavities and conductors of the body, such as nose, mouth, or trachea
• abnormal results in liver blood tests, increase in the level of “creatinine” in the blood

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

• blood cancer that develops rapidly and affects blood cells (acute myeloid leukemia), bone marrow disease that affects blood cells (myelodysplastic syndrome), cancer of the mouth or lips

Reporting side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through thenational notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the label and the box.

Store in refrigerator (between 2°C and 8°C). Do not freeze.

After dilution:

The chemical and physical stability was checked during its use, for a period of 24 hours between 2°C and 8°C. From a microbiological point of view, the product should be used immediately. If it is not used immediately, the storage periods during its use and the conditions before using it are the responsibility of the person using it and should not be greater than 24 hours between 2°C and 8°C. Partially used vials should be discarded.

Do not use this medication if you observe evidence of precipitation or presence of particles.

Medications should not be thrown into the drains or trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of ZOLSKETIL pegylated liposomal

• The active ingredient is hydrochloride of doxorubicin. One ml of ZOLSKETIL pegylated liposomal contains 2 mg of hydrochloride of doxorubicin in a pegylated liposomal formulation.
• The other components areN-(carbonyl-methoxy polyethylene glycol-2000)-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine,sodium salt (MPEG2000-DSPE), hydrogenated soy phosphatidylcholine (HSPC), cholesterol, ammonium sulfate, sucrose, histidine, water for injection, concentrated hydrochloric acid (for pH adjustment) and sodium hydroxide (for pH adjustment).

See section 2.

ZOLSKETIL pegylated liposomal: vials providing 10ml (20mg) or 25ml (50mg).

Appearance of ZOLSKETIL pegylated liposomal and contents of the package

This medicine is a translucent and red dispersion contained in a transparent glass vial. ZOLSKETIL pegylated liposomal is available in glass vials as individual packaging or packaging of 10 vials.

Only some sizes of packaging may be commercially available.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n, Edifici Est 6th floor,

Barcelona, 08039,

Spain

Responsible for manufacturing

Accord Healthcare Polska Sp. z o.o.

ul. Lutomierska 50, Pabianice, 95-200

Poland

Accord Healthcare B.V.

Winthontlaan 200, Utrecht, 3526KV

Netherlands

Last review date of this leaflet: {MM/YYYY}

Further information on this medicine is available on the European Medicines Agency (EMEA) websitehttp://www.emea.europa.eu/.

This information is intended solely for medical professionals or healthcare professionals (see section 3):

Care should be taken when handling a solution of ZOLSKETIL pegylated liposomal. Gloves should be used. In the event that ZOLSKETIL pegylated liposomal comes into contact with skin or mucous membranes, the affected area should be washed immediately with water and soap. ZOLSKETIL pegylated liposomal should be handled and disposed of as other anticancer drugs.

Determine the dose of ZOLSKETIL pegylated liposomal to be administered (based on the recommended dose and the patient's body surface area). Take the appropriate volume of ZOLSKETIL pegylated liposomal in a sterile syringe. Strict aseptic measures should be followed since ZOLSKETIL pegylated liposomal does not contain any preservative or bacteriostatic agent. The appropriate dose of ZOLSKETIL pegylated liposomal should be diluted in a 5% glucose infusion solution (50 mg/ml) before administration. For doses <90 mg, dilute ZOLSKETIL pegylated liposomal in 250ml, and for doses≥90 mg, dilute ZOLSKETIL pegylated liposomal in 500ml.

To minimize the risk of infusion reactions, the initial dose should be administered at a rate not exceeding 1mg/minute. If no infusion reaction is observed, subsequent infusions of ZOLSKETIL pegylated liposomal can be administered over a period of 60 minutes.

In the cancer clinical trial program, modification of the infusion was allowed in patients who experienced an infusion reaction as follows: 5% of the total dose was infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate was doubled during the next 15 minutes. If tolerated, the infusion was completed over the next hour for a total infusion time of 90 minutes.

If the patient experiences early symptoms or signs of infusion reaction, discontinue the infusion immediately, administer appropriate symptomatic treatment (antihistamine and/or short-acting corticosteroid) and resume at a slower rate.

The use of any diluent other than 5% glucose infusion solution (50 mg/ml), or the presence of any bacteriostatic agent, such as benzyl alcohol, may cause precipitation of ZOLSKETIL pegylated liposomal.

It is recommended that the ZOLSKETIL pegylated liposomal syringe be connected laterally to an intravenous infusion of 5% glucose solution (50 mg/ml). The infusion can be administered through a peripheral vein. Do not use with filters in the infusion line.