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

Patient Information Leaflet

Introduction

Package leaflet: Information for the user

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

doxorubicin hydrochloride

Read the entire leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only and must not be given to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any adverse reactions, consult your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the leaflet

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

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

ZOLSKETIL pegylated liposomal is an antitumour agent.

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

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

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

ZOLSKETIL pegylated liposomal contains a medicine capable of interacting with cells in such a way that it selectively kills cancer-affected cells. The doxorubicin hydrochloride in ZOLSKETIL pegylated liposomal is enclosed within tiny spheres called pegylated liposomes, which facilitate the release of the medicine from the bloodstream into cancerous tissue before reaching normal, healthy tissue.

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

Do not use ZOLSKETIL pegylated liposomal

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

Warnings and precautions

Tell your doctor if you have any of the following:

• if you are receiving treatment for heart or liver disease;
• if you have diabetes, as ZOLSKETIL pegylated liposomal contains sugar and your diabetes treatment may need to be adjusted;
• if you have Kaposi's sarcoma and have had your spleen removed;
• if you notice mouth 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 develop painful skin rashes with macular redness;
• if there is leakage of medication or vesicant substances from the vein into surrounding tissue;
• if you experience hand-foot syndrome (redness, swelling, and blisters (fluid accumulation between the upper layers of the skin) on the palms of the hands and soles of the feet).

Strategies to prevent and treat hand-foot syndrome include:

• soaking hands and/or feet in containers with cold water whenever possible (e.g., while watching television, reading, or listening to the radio);
• keeping hands and feet uncovered (without gloves, socks, etc.);
• staying in cool environments;
• taking cold 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-fitting footwear or high-heeled shoes.

Pyridoxine (Vitamin B6):

• vitamin B6 is available without a prescription;
• take 50–150 mg daily starting when you first notice redness or tingling.

Children and adolescents

ZOLSKETIL pegylated liposomal must not be used in children and adolescents, as it is unknown how the medicine will affect them.

Use of ZOLSKETIL pegylated liposomal with other medicines

Tell your doctor or pharmacist

• if you are taking or have recently taken any other medicines, including those obtained without a prescription;
• about any other anticancer treatments you are receiving or have received, as special care is needed with treatments that reduce white blood cell counts, as they may cause a further decrease in white blood cells. If you are unsure about the treatments you have received or the illnesses you have had, discuss this with your doctor.

Pregnancy and breastfeeding

Consult your doctor or pharmacist before using any medicine.

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

Women must avoid becoming pregnant and use contraception during treatment with ZOLSKETIL pegylated liposomal and for eight months after treatment ends. To prevent pregnancy in their partners, men must use contraception during and for at least six months after treatment with ZOLSKETIL pegylated liposomal.

Because doxorubicin hydrochloride may be harmful to infants, women must stop breastfeeding before starting treatment with ZOLSKETIL pegylated liposomal. Health experts recommend that women infected with HIV do not breastfeed their infants under any circumstances to avoid transmission of HIV.

Driving and use of machines

Do not drive or operate tools or machinery 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; essentially, "sodium-free".

3. How to use ZOLSKETIL pegylated liposomal

ZOLSKETIL pegylated liposomal is a formulation with particular characteristics. Therefore, it must not be interchanged with other medicines containing 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 meter of your body surface area (calculated from your height and weight). This 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 have received at least one prior therapy, you will be given ZOLSKETIL pegylated liposomal at a dose of 30 mg per square meter of your body surface area (calculated from your height and weight) as a 1-hour intravenous infusion on day 4 of the 3-week bortezomib regimen, 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 meter of your body surface area (calculated from your height and weight). This dose is repeated every 2 to 3 weeks for 2–3 months, and then as frequently as necessary to maintain improvement.

How ZOLSKETIL pegylated liposomal is administered

Your doctor will administer ZOLSKETIL pegylated liposomal to you as an intravenous infusion (drip) into a vein. Depending on the dose and indication, this may last from 30 minutes to more than one hour (i.e., 90 minutes).

If you use more ZOLSKETIL pegylated liposomal than you should

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

If you have any further questions about 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 everyone will experience them.

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

• severe allergic reaction which may include swelling of the face, lips, mouth, tongue or throat; difficulty swallowing or breathing; itchy rash (urticaria)
• inflammation and narrowing of the lung airways, causing cough, wheezing and difficulty breathing (asthma)
• flushing, sweating, chills or fever
• pain or discomfort in the chest
• back pain
• increase or decrease in blood pressure
• rapid heart rate
• seizures (convulsions)

Leakage of the injection fluid from the veins into the tissue beneath the skin may occur. If the infusion site stings or hurts while 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 fever, feel tired, or show signs of bruising or bleeding (very common)
• redness, swelling, peeling or pain upon touch, mainly in hands or feet (hand-foot syndrome). These effects are very common and sometimes severe. In severe cases, these effects may interfere with certain daily activities and may last up to 4 weeks or longer before resolving completely. Your doctor may delay the start and/or reduce the dose of your next treatment (see Strategies for preventing and treating hand-foot syndrome)
• mouth sores, severe diarrhea or vomiting or nausea (very common)
• infections (frequent), including lung infections (pneumonia) or infections that may affect your vision
• difficulty breathing (frequent)
• severe stomach pain (frequent)
• severe weakness (frequent)
• severe allergic reaction which may include swelling of the face, lips, mouth, tongue or throat; difficulty swallowing or breathing; itchy rash (urticaria) (uncommon)
• cardiac arrest (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 lead to swelling of the legs (uncommon)
• formation of blood clots in the blood vessels leading to the lungs, causing chest pain and difficulty breathing (uncommon)
• swelling, warmth or tenderness in an 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 over most of the body (toxic epidermal necrolysis) (rare)

Other adverse effects

Between infusions, the following may occur:

Very common adverse 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, low white blood cells may lead to a serious infection. Anaemia (decrease in red blood cells) may cause tiredness, and low platelets in the blood may 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, raised or reddened rash on the skin
• hair loss
• pain, including muscle and chest pain, joint, arm or leg pain
• feeling very tired

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

• infections, including serious body-wide infection (sepsis), lung infections, infections caused by the herpes zoster virus (shingles), a type of bacterial infection (Mycobacterium avium complex), urinary tract infection, fungal infections (including oral thrush and oral candidiasis), infection or inflammation of hair follicles, infection or irritation of the throat, infection of the nose, nasal passages or throat (common cold)
• low number of a type of white blood cells (neutrophils), with fever
• severe weight loss and muscle weakness, insufficient body water (dehydration), low levels of potassium, sodium or calcium in the blood
• feeling confused, anxious, depressed, difficulty sleeping
• nerve damage which may cause tingling, numbness, pain or loss of pain sensation, nerve pain, unusual skin sensations (such as tingling or prickling), reduced sensitivity, especially in the skin
• change in taste sensation, headache, feeling very sleepy with low energy, feeling dizzy
• inflammation of the eyes (conjunctivitis)
• rapid heart rate
• increase or decrease in blood pressure, facial flushing
• difficulty breathing which may occur after physical activity, nosebleeds, cough
• inflammation of the stomach lining or oesophagus, ulcers (sores) in the mouth, indigestion, difficulty swallowing, mouth pain, dry mouth
• skin problems, including dry or scaly skin, erythema, blisters or ulcers (sores) on the skin, itching, dark spots on the skin
• excessive sweating
• muscle spasms or muscle pains
• pain affecting 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 various body cavities and ducts, such as nose, mouth or trachea, feeling weak, general malaise, swelling due to fluid retention, sensation of swelling in hands, ankles or feet
• weight loss

When ZOLSKETIL pegylated liposomal is used as a single medicine, some of these adverse effects are less likely to occur, and some have never been reported.

Uncommon adverse effects (may affect up to 1 in 100 patients)

• infections caused by the herpes simplex virus (cold sores or genital herpes), fungal infections
• low number of all types of blood cells, increased 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
• seizures (convulsions), fainting
• unpleasant or painful sensation, especially to touch, drowsiness
• blurred vision, watery eyes
• sensation of rapid or irregular heartbeat (palpitations), heart muscle disease, heart damage
• tissue damage (necrosis) at the injection site, inflammation of veins causing swelling and pain, dizziness when sitting or standing up
• chest discomfort
• 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 colour (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 swelling, redness or pain) in body parts previously treated with radiotherapy or damaged as a result of intravenous chemotherapy injection

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

• infection occurring in people with a weakened immune system
• low number of blood cells produced in the bone marrow
• inflammation of the retina, which may cause changes in vision or blindness
• abnormal heart rhythm, abnormal ECG (electrocardiogram) trace which may occur with low heart rate, heart condition affecting heart rate and rhythm, bluish discoloration of the skin and mucous membranes caused by low oxygen concentration in the blood
• dilation of blood vessels
• sensation of tightness in the throat
• sores and swelling of the tongue, ulcers (sores) on the lips
• skin rash with fluid-filled blisters
• vaginal infection, redness of the scrotum
• problems with mucous membranes of various body cavities and ducts, such as nose, mouth or trachea
• abnormal results in liver blood tests, increased level of "creatinine" in the blood

Adverse effects with unknown frequency (cannot be estimated from available data)

• rapidly developing blood cancer affecting blood cells (acute myeloid leukaemia), bone marrow disease affecting blood cells (myelodysplastic syndrome), cancer of the mouth or lips

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide 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 expiry date stated on the label and carton.

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

After dilution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage periods during use and the conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2 °C to 8 °C. Partially used vials must be discarded.

Do not use this medicine if precipitation or particulate matter is observed.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This helps protect the environment.

6. Contents of the container and other information

Composition of ZOLSKETIL pegylated liposomal

• The active substance 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 soybean phosphatidylcholine (HSPC), cholesterol, ammonium sulfate, sucrose, histidine, water for injections, concentrated hydrochloric acid (for pH adjustment), and sodium hydroxide (for pH adjustment).

See section 2.

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

Appearance of ZOLSKETIL pegylated liposomal and contents of the container

This medicine is a translucent red dispersion contained in a clear glass vial. ZOLSKETIL pegylated liposomal is available in glass vials as single packs or packs of 10 vials.

Only certain pack sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center,

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

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

The Netherlands

Date of latest revision of this leaflet: {MM/YYYY}

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

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

Care must be taken when handling a solution of ZOLSKETIL pegylated liposomal. Gloves must be worn. If ZOLSKETIL pegylated liposomal comes into contact with skin or mucous membranes, wash the affected area immediately with water and soap. ZOLSKETIL pegylated liposomal must be handled and disposed of in the same manner 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). Withdraw the appropriate volume of ZOLSKETIL pegylated liposomal into a sterile syringe. Strict aseptic techniques must be followed, as ZOLSKETIL pegylated liposomal contains no preservative or bacteriostatic agent. The appropriate dose of ZOLSKETIL pegylated liposomal must be diluted in 5% glucose solution for infusion (50 mg/ml) prior to administration. For doses < 90 mg, dilute ZOLSKETIL pegylated liposomal in 250 ml; for doses ≥ 90 mg, dilute in 500 ml.

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

In the clinical trial program for breast cancer, modification of the infusion regimen was permitted 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 over the next 15 minutes. If tolerated, the infusion was completed over the following hour, resulting in a total infusion time of 90 minutes.

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

The use of any diluent other than 5% glucose solution for infusion (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 infusion set be connected via a side port to an intravenous line containing 5% glucose solution (50 mg/ml). The infusion may be administered through a peripheral vein. Do not use filters in the infusion line.