Caelyx pegylated liposomal

Package leaflet: Information for the user

Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion

doxorubicin hydrochloride
Please 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 questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

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

Caelyx pegylated liposomal is an antitumor agent.
Caelyx pegylated liposomal is used to treat breast cancer in patients at risk of
cardiac problems. Caelyx pegylated liposomal is also used to treat ovarian cancer. It
is used to kill tumor cells, reduce tumor size, delay tumor growth, and prolong survival.
Caelyx 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.
Caelyx pegylated liposomal is also used to improve symptoms of Kaposi's sarcoma,
including flattening, fading, and reduction in tumor size. Other symptoms of Kaposi's sarcoma, such as swelling around the tumor, may also improve or disappear.
Caelyx pegylated liposomal contains a substance capable of interacting with cells to selectively kill tumor cells. The doxorubicin hydrochloride contained in Caelyx pegylated
liposomal is enclosed within very small spheres called pegylated liposomes, which facilitate the delivery of the drug from the bloodstream to tumor tissue while minimizing dispersion into healthy tissue.

2. What you should know before taking Caelyx pegylated liposomal

Do not take Caelyx pegylated liposomal

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

Warnings and precautions
Inform your doctor if any of the following apply:

• if you are being treated for heart or liver disorders;
• if you have diabetes, as Caelyx pegylated liposomal contains sugar and your diabetes treatment may need to be adjusted accordingly;
• if you have Kaposi's sarcoma and your spleen has been removed;
• if you notice mouth ulcers, colour changes, or any other problems in your mouth.

Interstitial lung disease, including fatal cases, has been observed in patients treated with pegylated liposomal doxorubicin. Symptoms of interstitial lung disease include cough and shortness of breath, sometimes accompanied by fever, not caused by physical exertion. Seek immediate medical attention if you experience symptoms that could indicate interstitial lung disease.

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

Other medicines and Caelyx pegylated liposomal
Inform your doctor or pharmacist:

• if you are taking or have recently taken any other medicines, including those without a prescription;
• about all cancer treatments you are currently receiving or have previously received, as particular caution is required with treatments that reduce white blood cell counts, as they may further decrease the number of white blood cells. If you are unsure about treatments you have received or illnesses you have had, discuss this with your doctor.

Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Since the active substance in Caelyx pegylated liposomal, doxorubicin hydrochloride, may cause harm to the unborn child, it is important that you inform your doctor if you think you may be pregnant.
Women must avoid pregnancy and use effective contraception during treatment with Caelyx pegylated liposomal and for eight months after stopping treatment with Caelyx pegylated liposomal.
Men must use contraception during treatment with Caelyx pegylated liposomal and for six months after stopping Caelyx pegylated liposomal to prevent their partner from becoming pregnant.
Since doxorubicin hydrochloride may be harmful to infants, women must stop breastfeeding before starting treatment with Caelyx pegylated liposomal. Experts recommend that women with HIV infection should under no circumstances breastfeed their infants to prevent transmission of HIV.

Driving and using machines
Do not drive or operate tools or machinery if you feel tired or drowsy following treatment with Caelyx pegylated liposomal.

Caelyx pegylated liposomal contains soybean oil and sodium
Caelyx pegylated liposomal contains soybean oil. If you are allergic to peanuts or soy, do not use this medicine.
Caelyx pegylated liposomal contains less than 1 mmol (23 mg) of sodium per dose, i.e., “essentially sodium-free”.

3. How to take Caelyx pegylated liposomal

Caelyx pegylated liposomal is a unique formulation. It must not be used interchangeably with other formulations of doxorubicin hydrochloride.
How much Caelyx pegylated liposomal is given
If you are being treated for breast or ovarian cancer, Caelyx pegylated liposomal will be administered at a dose of 50 mg per square metre of your body surface area (based on your height and body weight). This dose will be repeated every 4 weeks for as long as your disease does not progress and you are able to tolerate the treatment.
If you are being treated for multiple myeloma and have previously received at least one prior therapy, Caelyx pegylated liposomal will be administered at a dose of 30 mg per square metre of your body surface area (based on your height and body weight) as a 1-hour intravenous infusion given immediately after the bortezomib infusion on day 4 of the 3-week bortezomib treatment regimen. The dose will be repeated for as long as you continue to respond satisfactorily and tolerate the treatment.
If you are being treated for Kaposi's sarcoma, Caelyx pegylated liposomal will be administered at a dose of 20 mg per square metre of your body surface area (based on your height and body weight). The dose will be repeated every 2 or 3 weeks for 2 or 3 months; thereafter, it will be repeated as needed to maintain improvement in your condition.
How Caelyx pegylated liposomal is administered
Caelyx pegylated liposomal will be administered by your doctor via intravenous infusion (drip) into a vein. Depending on the dose and indication, the infusion will last from 30 minutes to more than one hour (i.e., 90 minutes).
If you take more Caelyx pegylated liposomal than you should
Acute overdose worsens side effects such as mouth sores or reduction in white blood cells and platelets in the blood. Treatment will include administration of antibiotics, platelet transfusions, use of factors stimulating white blood cell production, and symptomatic treatment of mouth sores.
If you have any questions about the use of Caelyx pegylated liposomal, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
During infusion of Caelyx 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 airways in the lungs, resulting in cough, wheezing and shortness of breath (asthma)
• hot flushes, sweating, chills or fever
• chest pain or discomfort
• back pain
• high or low blood pressure
• rapid heartbeat
• seizures (convulsions)

Leakage of the infused liquid from the vein into surrounding tissues may occur. If the infusion causes discomfort or pain while you are receiving a dose of Caelyx pegylated liposomal, inform your doctor immediately.
Contact your doctor immediately if you experience any of the following serious side effects:

• fever, feeling tired, or signs of bruising or bleeding (very common)
• redness, swelling, peeling or tenderness, mainly in the hands or feet (hand-foot syndrome). These effects have been observed very commonly and sometimes are 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 consider delaying and/or reducing the dose of the next treatment (see below for strategies to prevent and treat hand-foot syndrome)
• mouth sores, severe diarrhoea, vomiting or nausea (very common)
• infections (common, including lung infections (pneumonia) or infections that may affect vision)
• shortness of breath (common)
• severe stomach pain (common)
• marked weakness (common)
• 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, causing shortness of breath and possibly swollen legs (uncommon)
• blood clot that travels to the lungs causing chest pain and shortness of breath (uncommon)
• swelling, warmth or tenderness in the soft tissues of the legs, sometimes with pain that worsens when standing or walking (rare)
• severe or potentially life-threatening skin rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genital organs (Stevens-Johnson syndrome) or affecting most of the body (toxic epidermal necrolysis) (rare)

Other side effects
Between infusions, the following side effects may occur:
Very common (may affect more than 1 in 10 patients):

• reduced number of white blood cells, which may increase the risk of infections. In rare cases, low white blood cell count may lead to a serious infection. Anaemia (reduction in red blood cells) may cause tiredness, and reduced platelets in the blood may increase the risk of bleeding. Due to potential changes in blood cells, you will have regular blood tests.
• reduced appetite
• constipation
• skin rashes, including skin redness, allergic skin rashes, red or raised rashes on the skin
• hair loss
• pain, including muscle, chest, joint, arm or leg pain
• feeling extremely tired

Common (may affect up to 1 in 10 patients):

• infections, including severe body-wide infection (sepsis), lung infections, herpes zoster virus infections (shingles), a type of bacterial infection (Mycobacterium avium complex infection), urinary tract infections, fungal infections (including oral thrush and candidiasis), hair follicle infections, throat infection or irritation, infection of the nose, sinuses or throat (common cold)
• low number of a type of white blood cells (neutrophils) with fever
• severe weight loss and muscle wasting, insufficient body water (dehydration), low levels of potassium, sodium or calcium in the blood
• confusion, anxiety, depression, difficulty sleeping
• nerve damage, which may cause tingling, numbness, pain or loss of sensation, nerve pain, unusual skin sensations (such as tingling or crawling sensations), reduced sensation and sensitivity, especially in the skin
• altered sense of taste, headache, feeling extremely drowsy with low energy, dizziness
• eye inflammation (conjunctivitis)
• rapid heartbeat
• high or low blood pressure, hot flushes
• shortness of breath, which may be caused by physical activity, nosebleeds, cough
• inflammation of the lining of the stomach and oesophagus, mouth ulcers (aphthae), indigestion, difficulty swallowing, mouth pain, dry mouth
• skin problems, including peeling or dry skin, skin redness, blisters or ulcers (urticaria) on the skin, itching, dark spots on the skin
• excessive sweating
• muscle spasms or pain
• pain, including muscle, bone or back pain
• pain during urination
• allergic reaction to the infusion, flu-like illness, chills, inflammation of the linings of cavities and passages inside the body such as nose, mouth, trachea, feeling weak, general feeling of discomfort, swelling due to fluid accumulation in the body, swollen hands, ankles or feet
• weight loss

When Caelyx pegylated liposomal is used alone, some of these side effects are less likely, and some do not occur at all.
Uncommon (affects up to 1 in 100 patients):

• herpes simplex virus infections (cold sores or genital herpes), fungal infection
• 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 part of the body
• seizures (convulsions), fainting
• unpleasant or painful sensation, especially on 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, vein inflammation causing swelling and pain, dizziness when sitting or standing up
• chest discomfort
• flatulence, inflamed gums (gingivitis)
• skin problems or rashes, including cracked or peeling skin, allergic skin rashes, ulcers or hives on the skin, skin depigmentation, changes in natural skin colouring (pigmentation), small red or purple spots caused by bleeding under the skin, nail problems, acne
• muscle weakness
• chest pain
• irritation or pain at the injection site
• facial swelling, high body temperature
• return of symptoms (such as inflammation, redness or pain) in an area previously irradiated with radiotherapy or previously damaged by a chemotherapy injection into a vein

Rare (affects up to 1 in 1,000 patients):

• infection occurring in people with weakened immune systems
• low number of blood cells produced in the bone marrow
• inflamed retina, which may cause changes in vision or blindness
• abnormal heart rhythm, abnormal heart tracing on ECG (electrocardiogram) with possible slow heartbeat, heart condition affecting heartbeat and rhythm, blue colour of the skin and mucous membranes due to low oxygen levels in the blood
• dilation of blood vessels
• sensation of tightness in the throat
• swollen and painful tongue, ulcers (sores) on the lips
• skin rash with fluid-filled blisters
• vaginal infection, redness of the scrotum
• problems with the linings of cavities and passages inside the body, such as nose, mouth or trachea
• abnormal liver function tests, increased level of "creatinine" in the blood

Not known (frequency cannot be estimated from the 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
• cough and shortness of breath, sometimes accompanied by fever, not caused by physical activity (interstitial lung disease)

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

Strategies to prevent and treat hand-foot syndrome include:

• when possible, immerse hands and/or feet in a basin of cold water (e.g., while watching television, reading or listening to the radio);
• keep hands and feet uncovered (no gloves, socks, etc.);
• stay in cool environments;
• take cold baths during hot periods;
• avoid vigorous exercises that may cause trauma to the feet (e.g., jogging);
• avoid exposing the skin to very hot water (e.g., hot tubs, saunas);
• avoid tight-fitting or high-heeled shoes.

Pyridoxine (Vitamin B6):

• vitamin B6 is available without a prescription;
• take 50–150 mg daily, starting at the first signs of redness or tingling.

5. How to store Caelyx pegylated liposomal

Keep Caelyx pegylated liposomal out of the sight and reach of children.
Store in a refrigerator (2°C - 8°C). Do not freeze.
After dilution:
Chemical and physical in-use stability has been demonstrated for 24 hours at temperatures between 2°C
and 8°C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage times and conditions of the diluted solution prior to use are the responsibility of the user and must not exceed 24 hours when stored at temperatures between 2°C and 8°C. Partially used vials must be discarded.
Do not use this medicine after the expiry date stated on the label and outer carton.
Do not use this medicine if you notice any precipitate or other types of particles.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Caelyx pegylated liposomal contains

• The active substance is doxorubicin hydrochloride. One ml of Caelyx pegylated liposomal contains 2 mg of doxorubicin hydrochloride in a pegylated liposomal formulation.
• The excipients are α-(2-[1,2-distearoyl-sn-glycero(3)-phospho]ethylcarbamoyl)-ω-methoxypoly(oxyethylene)-40 sodium salt (MPEG-DSPE), fully hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, ammonium sulfate, sucrose, histidine, water for injections, hydrochloric acid (for pH adjustment), and sodium hydroxide (for pH adjustment). See section 2.

Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion: vials providing a volume of 10 ml (20 mg) or 25 ml (50 mg).
Description of the appearance of Caelyx pegylated liposomal and contents of the pack
Caelyx pegylated liposomal is sterile, translucent, and red. Caelyx pegylated liposomal is available in single glass vials or packs containing 10 vials.
Not all pack sizes may be marketed.
Marketing Authorization Holder
Baxter Holding B.V.
Kobaltweg 49,
3542 CE Utrecht,
The Netherlands.
Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium.
Baxter Oncology GmbH
Kantstrasse 2
33790 Halle/Westfalen
Germany

For further information on Caelyx pegylated liposomal, contact the local representative of the marketing authorization holder:
België/Belgique/Belgien Lietuva
Baxter Belgium SPRL/BVBA UAB „Baxter Lithuania“
Tél/Tel: +32 (0)2 386 80 00 Tel: +37052527100
[email protected]
България Luxembourg/Luxemburg
Baxter Holding B.V. Baxter Belgium SPRL/BVBA
Teл.: +31 (0)30 2488 911 Tél/Tel: +32 (0)2 386 80 00
[email protected]
Česká republika Magyarország
BAXTER CZECH spol. s r.o. Baxter Hungary Kft.
Tel: +420 225 774 111 Tel: +36 1 202 1980
Danmark Malta
Baxter A/S Baxter Holding B.V.
Tlf: +45 4816 6400 Tel: +44 (0)1635 206345
Deutschland Nederland
Baxter Deutschland GmbH Baxter B.V.
Tel: +49 (0)89 31701-0 Tel: +31 (0)30 2488 911
[email protected] [email protected]
Eesti Norge
OÜ Baxter Estonia Baxter AS
Tel: +372 651 5120 Tlf: +47 22 58 48 00
Ελλάδα Österreich
Baxter (Hellas) Ε.Π.Ε., Baxter Healthcare GmbH
Τηλ: +30 210 28 80 000 Tel: +43 1 71120 0
[email protected]
España Polska
Baxter S.L. Baxter Polska Sp. z o.o.
Tel: +34 91 678 93 00 Tel: +48 22 488 37 77
France Portugal
Baxter SAS Baxter Médico Farmacêutica, Lda.
Tél: +33 1 34 61 50 50 Tel: +351 21 925 25 00
Hrvatska România
Baxter Healthcare d.o.o. BAXTER HEALTHCARE SRL
Tel: +385 1 6610314 Tel: +40 372 302 053
Ireland Slovenija
Baxter Holding B.V. Baxter d.o.o.
Tel: +44 (0)1635 206345 Tel: +386 1 420 16 80
Ísland Slovenská republika
Baxter Medical AB Baxter Slovakia s.r.o.
Sími: +46 8 632 64 00 Tel: +421 2 32 10 11 50
Italia Suomi/Finland
Baxter S.p.A. Baxter Oy
Tel: +390632491233 Puh/Tel: +358 (09) 862 111
Κύπρος Sverige
Baxter Holding B.V. Baxter Medical AB
Τηλ: +31 (0)30 2488 911 Tel: +46 (0)8 632 64 00
Latvija United Kingdom (Northern Ireland)
Baxter Latvia SIA Baxter Holding B.V.
Tel: +371 677 84784 Tel: +44 (0)1635 206345

This leaflet was last approved on
More detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA): https://www.ema.europa.eu/en
The following information is intended exclusively for physicians and healthcare professionals (see section 3):
Caelyx pegylated liposomal dispersion must be handled with care. Gloves must be worn.
If Caelyx pegylated liposomal comes into contact with skin or mucous membranes, immediately wash thoroughly with soap and water. Caelyx pegylated liposomal must be handled and disposed of according to the precautions recommended for other antineoplastic agents.
Determine the required dose of Caelyx pegylated liposomal (according to the recommended dose and the patient's body surface area). Withdraw the correct volume of Caelyx pegylated liposomal using a sterile syringe. This must be done under strict aseptic conditions, as Caelyx pegylated liposomal contains neither preservatives nor bacteriostatic agents. Prior to administration, the correct dose of Caelyx pegylated liposomal must be diluted in 5% glucose solution (50 mg/ml) for intravenous infusion. For doses < 90 mg, dilute Caelyx pegylated liposomal in 250 ml; for doses ≥ 90 mg, dilute in 500 ml.
To reduce the risk of infusion reactions, the initial dose should be administered at a rate not exceeding 1 mg/min. If no infusion reaction occurs, subsequent infusions of Caelyx pegylated liposomal may be given over a period of 60 minutes.
In the clinical trial program for breast cancer, modification of the infusion regimen was allowed in patients who experienced an infusion reaction as follows: 5% of the total dose was administered slowly over the first 15 minutes. If tolerated without reactions, the infusion rate was doubled for 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 symptoms or signs of an infusion reaction, immediately stop the infusion, administer appropriate premedication (antihistamines and/or short-acting corticosteroids), and resume the infusion at a slower rate.
The use of diluents other than 5% glucose solution (50 mg/ml) for intravenous infusion or the presence of any bacteriostatic agent, such as benzyl alcohol, may cause precipitation of Caelyx pegylated liposomal.
It is recommended to connect the infusion line containing Caelyx pegylated liposomal to the side port of a 5% glucose (50 mg/ml) intravenous infusion. The infusion can be administered via a peripheral vein. Do not use in-line filters.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE
TERMS OF THE MARKETING AUTHORISATION(S)

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for doxorubicin, the scientific conclusions of the Committee for Human Medicinal Products (CHMP) are as follows:
In view of available data on interstitial lung disease from the literature and spontaneous reports, including in some cases a close temporal association, the PRAC considers that a causal relationship between pegylated liposomal doxorubicin and interstitial lung disease is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing pegylated liposomal doxorubicin should be updated accordingly.
The CHMP agrees with the scientific conclusions of the PRAC.

Reasons for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions for doxorubicin, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing doxorubicin remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).