ZOLSKETIL PEGYLATED LIPOSOMAL 2 mg/ml CONCENTRATE FOR DISPERSION FOR INFUSION

Introduction

Package Leaflet: Information for the User

ZOLSKETIL pegylated liposomal 2mg/ml concentrate for dispersion for infusion

doxorubicin hydrochloride

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is ZOLSKETIL pegylated liposomal and what is it used for

ZOLSKETIL pegylated liposomal is an anti-tumour agent.

ZOLSKETIL pegylated liposomal is used to treat breast cancer in patients with a risk of heart problems. ZOLSKETIL pegylated liposomal is also used to treat ovarian cancer. It is used to kill the cells affected by cancer, reduce the size of the tumour, delay the growth of the tumour and increase survival.

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

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

ZOLSKETIL pegylated liposomal contains a medicine that interacts with cells in such a way that it selectively kills the cells affected by cancer. Doxorubicin hydrochloride in ZOLSKETIL pegylated liposomal is enclosed in tiny spheres called pegylated liposomes that facilitate the release of the medicine from the bloodstream into the cancerous tissue before it reaches normal and healthy tissue.

2. What you need to know before you use ZOLSKETIL pegylated liposomal

Do not use ZOLSKETIL pegylated liposomal

• if you are allergic to doxorubicin hydrochloride, peanut or soy, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Tell your doctor if you have:

• if you are receiving any treatment for a 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 the mouth.
• if your bone marrow is not producing enough blood cells
• if you have a cancer in which the bone marrow produces abnormal blood cells
• if you suffer from painful skin rashes with red spots
• if there are leaks of medicine or vesicant substances from the vein into the surrounding tissue
• if you have hand-foot syndrome (redness, swelling and blisters on the palms of the hands and soles of the feet)

Strategies to prevent and treat 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 the feet (e.g. jogging);
• avoiding exposure of the skin to very hot water (e.g. hot tubs, saunas);
• avoiding tight footwear or high-heeled shoes.

Pyridoxine (Vitamin B6):

• Vitamin B6 is available without a prescription;
• take 50-150 mg per day starting when the first signs of redness or tingling appear.

Children and adolescents

ZOLSKETIL pegylated liposomal must not be used in children and adolescents, as it is not known how this medicine affects them.

Using ZOLSKETIL pegylated liposomal with other medicines

Tell your doctor or pharmacist

• if you are using or have recently used any other medicines, including those obtained without a prescription;
• about any other anti-cancer treatments you are receiving or have received, as special care is needed with treatments that reduce the number of white blood cells, as they may cause a further reduction in the number of white blood cells. If you are not sure about the treatments you have received or the diseases you have had, discuss this with your doctor.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Since the active substance doxorubicin hydrochloride in ZOLSKETIL pegylated liposomal may cause birth defects, it is important that you contact your doctor if you think you are pregnant.

Women must avoid becoming pregnant and use contraceptive methods while being treated with ZOLSKETIL pegylated liposomal and for 8 months after finishing the treatment. To avoid pregnancy of their partners, men must use contraceptive methods during and up to 6 months after treatment with ZOLSKETIL pegylated liposomal.

Since doxorubicin hydrochloride can be harmful to breast-fed babies, women must stop breast-feeding before starting treatment with ZOLSKETIL pegylated liposomal. Health experts recommend that HIV-infected women should not breast-feed their babies under any circumstances to avoid transmitting HIV.

Driving and using machines

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

ZOLSKETIL pegylated liposomal contains soybean oil and sodium

ZOLSKETIL pegylated liposomal contains soybean oil. Do not use this medicine if you are allergic to peanut or soy.

ZOLSKETIL pegylated liposomal contains less than 1 mmol of sodium (23 mg) per dose; i.e. it is essentially “sodium-free”.

3. How to use ZOLSKETIL pegylated liposomal

ZOLSKETIL pegylated liposomal is a formulation with particular characteristics. Therefore, it must not be exchanged with other medicines that also contain doxorubicin hydrochloride.

How much ZOLSKETIL pegylated liposomal is administered

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

If you are being treated for multiple myeloma, and have received at least one prior treatment, you will be given ZOLSKETIL pegylated liposomal at a dose of 30 mg per square metre of your body surface area (based on your height and weight) in a 1-hour intravenous infusion on day 4 of the 3-week bortezomib regimen and immediately after 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 given ZOLSKETIL pegylated liposomal at a dose of 20 mg per square metre of your body surface area (which is calculated from your height and weight). The dose is repeated every 2 to 3 weeks for 2-3 months, and then as often as necessary to maintain improvement of your condition.

How ZOLSKETIL pegylated liposomal is administered

Your doctor will give you ZOLSKETIL pegylated liposomal through a drip (infusion) in a vein. Depending on the dose and indication, this may take from 30 minutes to more than 1 hour (i.e. 90 minutes).

If you use more ZOLSKETIL pegylated liposomal than you should

Acute overdosing worsens side effects such as mouth ulcers or reduces 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 the production of white blood cells and symptomatic treatment of mouth ulcers.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

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

• severe allergic reaction that can include swelling in the face, lips, mouth, tongue, or throat; difficulty swallowing or breathing; pruritic exanthem (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 heartbeat
• seizures (convulsions)

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

Contact your doctor immediately if you notice any of the following serious adverse effects:

• you have a fever, feel tired, or show signs of bruising or bleeding (very frequent)
• redness, swelling, peeling, or pain to the touch, mainly on hands or feet (hand-foot syndrome). These effects have been seen very frequently and, sometimes, are serious. In severe cases, these effects can interfere with certain daily activities and can last up to 4 weeks or more before they are completely resolved. The doctor may delay the start and/or reduce the dose of the next treatment (see Strategies to prevent and treat hand-foot syndrome)
• sores in the mouth, severe diarrhea, or vomiting or nausea (very frequent)
• infections (frequent), including pulmonary infections (pneumonia) or infections that can affect your vision
• difficulty breathing (frequent)
• severe stomach pain (frequent)
• severe weakness (frequent)
• severe allergic reaction that can include swelling in the face, lips, mouth, tongue, or throat; difficulty swallowing or breathing; pruritic exanthem (urticaria) (infrequent)
• cardiac arrest (the heart stops beating); heart failure, in which the heart does not pump enough blood to the rest of the body, which can cause difficulty breathing and can cause swelling of the legs (infrequent)
• formation of blood clots that reach the lungs, causing chest pain and difficulty breathing (infrequent)
• swelling, heat, or pain to the touch in some area of the leg, sometimes with pain that worsens when standing or walking (rare)
• severe or potentially life-threatening 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 Adverse Effects

In the time between infusions, the following may occur:

Very Frequent Adverse Effects(may affect more than 1 in 10 patients)

• decrease in the number of white blood cells, which can increase the chances of infection. In rare cases, the decrease in white blood cells can lead to a severe infection. Anemia (decrease in red blood cells) can cause fatigue, and a decrease in platelets in the blood can increase the risk of bleeding. Due to possible changes in your blood cells, you will undergo regular blood tests
• loss of appetite
• constipation
• skin rashes, including redness of the skin, allergic skin rash, bumpy or red rash on the skin
• hair loss
• pain, including muscle pain and chest pain, joint pain, arm or leg pain
• feeling of great fatigue

Frequent Adverse Effects(may affect up to 1 in 10 patients)

• infections, including severe infection throughout the body (sepsis), pulmonary infections, infections caused by the herpes zoster virus (herpes), a type of bacterial infection (infection by Mycobacterium avium complex), urinary tract infection, fungal infections (including thrush and oral thrush in the mouth), infection of the hair follicles, infection or irritation of the throat, infection of the nose, nasal passages, or throat (cold)
• low number of a type of white blood cell (neutrophils), with fever
• severe weight loss and muscle weakness, insufficient water in the body (dehydration), low levels of potassium, sodium, or calcium in the blood
• feeling of confusion, anxiety, depression, difficulty sleeping
• nerve damage that can cause tingling, numbness, pain, or loss of sensation, nerve pain, strange sensation on the skin (such as tingling or prickling), decreased sensitivity, especially on the skin
• change in taste, headache, feeling very sleepy with little energy, feeling dizzy
• inflammation of the eyes (conjunctivitis)
• rapid heartbeat
• increase or decrease in blood pressure, facial redness
• difficulty breathing that can appear after physical activity, nasal bleeding, cough
• inflammation of the gastric mucosa or esophagus, ulcers (sores) in the mouth, indigestion, difficulty swallowing, mouth pain, dry mouth
• skin problems or rashes, including dry or scaly skin, allergic rash, ulcers (sores) or blisters on the skin, skin discoloration, change in the natural color (pigmentation) of the skin, small red or purple spots caused by bleeding under the skin, nail problems, acne
• excessive sweating
• muscle spasms or pain
• pain that affects muscles, bones, or back
• pain when urinating
• allergic reaction to the infusion of the medicine, flu-like illness, chills, inflammation of the mucous membranes of different body cavities and ducts, such as the nose, mouth, or trachea, feeling of weakness, general feeling of discomfort, swelling caused by fluid retention, feeling of 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 adverse effects will occur, and some of them have never occurred.

Infrequent Adverse Effects(may affect up to 1 in 100 patients)

• infections caused by the simple herpes virus (cold sores or genital herpes), fungal infection
• low number of all types of blood cells, increased number of 'platelets' (cells that help blood clot)
• allergic reaction
• high level of potassium in the blood, low level of magnesium in the blood
• nerve damage that affects more than one area of the body
• seizures (convulsions), fainting
• unpleasant or painful sensation, especially to the touch, drowsiness
• blurred vision, watery eyes
• feeling of rapid or irregular heartbeat (palpitations), heart muscle disease, heart damage
• tissue damage (necrosis) at the injection site, inflammation of the veins that causes swelling and pain, feeling of dizziness when sitting or standing
• discomfort in the chest
• flatulence, inflamed gums (gingivitis)
• skin problems or rashes, including dry or scaly skin, allergic rash, ulcers (sores) or blisters on the skin, skin discoloration, change in the natural color (pigmentation) of the skin, 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 parts of the body that have been previously treated with radiation therapy or that have suffered damage as a result of an intravenous injection of chemotherapy

Rare Adverse 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 produced in the bone marrow
• inflammation of the retina, which can cause changes in vision or blindness
• abnormal heartbeat, abnormal tracing on an ECG (electrocardiogram) that can occur with low heart rate, heart problem that affects heart rate and rhythm, bluish discoloration of the skin and mucous membranes caused by low oxygen concentration in the blood
• dilation of blood vessels
• feeling of pressure in the throat
• sores and swelling on the tongue, ulcers (sores) on the lips
• skin rash with fluid-filled blisters
• vaginal infection, redness of the scrotum
• problems with the mucous membranes of different body cavities and ducts, such as the nose, mouth, or trachea
• abnormal results in liver blood tests, increased level of "creatinine" in the blood

Adverse 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), mouth or lip cancer

Reporting Adverse Effects

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

5. Storage of ZOLSKETIL pegylated liposomal

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

Do not use this medicine after the expiration date that appears on the label and carton.

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

After dilution:

The chemical and physical stability has been verified for use, for a period of 24 hours between 2°C and 8°C. From a microbiological point of view, the product must be used immediately. If it is not used immediately, the storage periods during use and the conditions before use are the responsibility of the user and should not exceed 24 hours between 2°C and 8°C. Partially used vials must be discarded.

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

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of ZOLSKETIL pegylated liposomal

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

See section 2.

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

Appearance of ZOLSKETIL pegylated liposomal and Package Contents

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

Not all pack sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n, Edifici Est 6ª planta,

Barcelona, 08039,

Spain

Manufacturer

Accord Healthcare Polska Sp. z o.o.

ul. Lutomierska 50, Pabianice, 95-200

Poland

Accord Healthcare B.V.

Winthontlaan 200, Utrecht, 3526KV

Netherlands

Date of the last revision of this prospectus: {MM/YYYY}

Detailed information about this medicine is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

This information is intended only for doctors or healthcare professionals (see section 3):

Caution should be exercised when handling a solution of ZOLSKETIL pegylated liposomal. The use of gloves is required. In case ZOLSKETIL pegylated liposomal comes into contact with skin or mucous membranes, wash the affected area immediately with water and soap. ZOLSKETIL pegylated liposomal should be handled and disposed of as other anticancer medicines.

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 have any preservative or bacteriostatic agent present. The appropriate dose of ZOLSKETIL pegylated liposomal should be diluted in a 5% glucose solution for infusion (50 mg/ml) before administration. For doses <90 mg, dilute zolsketil pegylated liposomal in 250 ml, and for doses ≥ 90 500 ml.< p>

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

In the clinical trial program for breast cancer, it was allowed to modify the infusion in those patients who experienced an infusion reaction as follows: 5% of the total dose was infused slowly over the first 15 minutes. If it was tolerated without reaction, the infusion rate was doubled over the next 15 minutes. If it was 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 an infusion reaction, the infusion should be immediately interrupted, appropriate symptomatic treatment should be administered (antihistamine and/or short-acting corticosteroid), and the infusion should be resumed at a slower rate.

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

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