Pegylated Liposomal Doxorubicin

ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
1. NAME OF THE MEDICINAL PRODUCT
Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of Caelyx pegylated liposomal contains 2 mg doxorubicin hydrochloride in a pegylated

liposomal formulation.
Caelyx pegylated liposomal is doxorubicin hydrochloride encapsulated in liposomes with

surface-bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protects
liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood
circulation time.
Excipients with known effect

Contains fully hydrogenated soy phosphatidylcholine (from soyabean) – see section 4.3.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion (sterile concentrate)
The dispersion is sterile, translucent and red.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Caelyx pegylated liposomal is indicated:

- As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac
risk.
- For treatment of advanced ovarian cancer in women who have failed a first-line platinum-based
chemotherapy regimen.
- In combination with bortezomib for the treatment of progressive multiple myeloma in patients
who have received at least one prior therapy and who have already undergone or are unsuitable
for bone marrow transplant.
- For treatment of AIDS-related Kaposi’s sarcoma (KS) in patients with low CD4 counts
(< 200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease.
Caelyx pegylated liposomal may be used as first-line systemic chemotherapy, or as second line
chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to,
prior combination systemic chemotherapy comprising at least two of the following agents: a vinca
alkaloid, bleomycin and standard doxorubicin (or other anthracycline).
4.2 Posology and method of administration
Caelyx pegylated liposomal should only be administered under the supervision of a qualified
oncologist specialised in the administration of cytotoxic agents.
Caelyx pegylated liposomal exhibits unique pharmacokinetic properties and must not be used
interchangeably with other formulations of doxorubicin hydrochloride.
2
Posology
Breast cancer/Ovarian cancer
Caelyx pegylated liposomal is administered intravenously at a dose of 50 mg/m2 once every 4 weeks
for as long as the disease does not progress and the patient continues to tolerate treatment.
Multiple myeloma
Caelyx pegylated liposomal is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen
as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen
consists of 1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as
patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be
delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.
AIDS-related KS
Caelyx pegylated liposomal is administered intravenously at 20 mg/m2 every two-to-three weeks.
Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannot
be ruled out. Treatment of patients for two-to-three months is recommended to achieve a therapeutic
response. Continue treatment as needed to maintain a therapeutic response.
For all patients

If the patient experiences early symptoms or signs of infusion reaction (see sections 4.4 and 4.8),
immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short
acting corticosteroid) and restart at a slower rate.
Guidelines for Caelyx pegylated liposomal dose modification

To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or
haematological toxicity, the dose may be reduced or delayed. Guidelines for Caelyx pegylated
liposomal dose modification secondary to these adverse effects are provided in the tables below. The
toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria
(NCI-CTC).
The tables for PPE (Table 1) and stomatitis (Table 2) provide the schedule followed for dose
modification in clinical trials in the treatment of breast or ovarian cancer (modification of the
recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS-related KS, the
recommended 2 to 3 week treatment cycle can be modified in a similar manner.
The table for haematological toxicity (Table 3) provides the schedule followed for dose modification
in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in
patients with AIDS-KS is provided following Table 4.
Table 1. Palmar–Plantar erythrodysesthesia

Week after prior Caelyx pegylated liposomal dose
Toxicity grade at Week 4 Week 5 Week 6
current assessment
Grade 1 Redose unless Redose unless Decrease dose by
(mild erythema, patient has patient has 25%; return to
swelling, or experienced a previous experienced a previous 4 week interval
desquamation not grade 3 or 4 skin grade 3 or 4 skin
interfering with daily toxicity, in which case toxicity, in which case
activities) wait an additional wait an additional
week week
3
Grade 2 Wait an additional Wait an additional Decrease dose by
(erythema, week week 25%; return to
desquamation, or 4 week interval
swelling interfering
with, but not precluding
normal physical
activities; small blisters
or ulcerations less than
2 cm in diameter)
Grade 3 Wait an additional Wait an additional Withdraw patient
(blistering, ulceration, week week
or swelling interfering
with walking or normal
daily activities; cannot
wear regular clothing)
(diffuse or local process week week
causing infectious
complications, or a
bedridden state or
hospitalisation)
Table 2. Stomatitis
Week after prior Caelyx pegylated liposomal dose
Toxicity grade at Week 4 Week 5 Week 6
current assessment
Grade 1 Redose unless Redose unless Decrease dose by
(painless ulcers, patient has patient has 25%; return to
erythema, or mild experienced a previous experienced a previous 4 week interval or
soreness) grade 3 or 4 stomatitis grade 3 or 4 stomatitis withdraw patient per
in which case wait an in which case wait an physician’s assessment
additional week additional week
Grade 2 Wait an additional Wait an additional Decrease dose by
(painful erythema, week week 25%; return to
oedema, or ulcers, but 4 week interval or
can eat) withdraw patient per
physician’s assessment
(painful erythema, week week
edema, or ulcers, but
cannot eat)
(requires parenteral or week week
enteral support)
Table 3. Haematological toxicity (ANC or platelets) – Management of patients with breast or

ovarian cancer
GRADE ANC PLATELETS MODIFICATION
Grade 1 1,500 – 1,900 75,000 – 150,000 Resume treatment with no dose
reduction.
Grade 2 1,000 – < 1,500 50,000 – < 75,000 Wait until ANC ≥ 1,500 and platelets
≥ 75,000; redose with no dose
reduction.
Grade 3 500 – < 1,000 25,000 – < 50,000 Wait until ANC ≥ 1,500 and platelets
≥ 75,000; redose with no dose
reduction.
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Grade 4 < 500 < 25,000 Wait until ANC ≥ 1,500 and platelets
≥ 75,000; decrease dose by 25% or
continue full dose with growth factor
support.
For multiple myeloma patients treated with Caelyx pegylated liposomal in combination with
bortezomib who experience PPE or stomatitis, the Caelyx pegylated liposomal dose should be
modified as described in Table 1 and 2 above respectively. Table 4, below provides the schedule
followed for other dose modifications in the clinical trial in the treatment of patients with multiple
myeloma receiving Caelyx pegylated liposomal and bortezomib combination therapy. For more
detailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib.
Table 4. Dosage adjustments for Caelyx pegylated liposomal + bortezomib combination

therapy - patients with multiple myeloma
Patient status Caelyx pegylated liposomal Bortezomib
Fever ≥ 38 C and ANC
○
Do not dose this cycle if before Reduce next dose by 25%.
< 1,000/mm3 day 4; if after day 4, reduce
next dose by 25%.
On any day of medicine Do not dose this cycle if before Do not dose; if 2 or more doses
administration after day 1 of day 4; if after day 4 reduce next are not given in a cycle, reduce
each cycle: dose by 25% in the following dose by 25% in following
Platelet count < 25,000/mm3 cycles if bortezomib is reduced cycles.
Haemoglobin < 8 g/dl for haematologic toxicity.*
ANC < 500/mm3
Grade 3 or 4 non-haematologic Do not dose until recovered to Do not dose until recovered to
medicine related toxicity grade < 2 and reduce dose by grade < 2 and reduce dose by
25% for all subsequent doses. 25% for all subsequent doses.
Neuropathic pain or peripheral No dosage adjustments. See the SPC for bortezomib.
neuropathy
* for more information on bortezomib dosing and dosage adjustment, see the SPC for bortezomib
For AIDS-KS patients treated with Caelyx pegylated liposomal, haematological toxicity may require
dose reduction or suspension or delay of therapy. Temporarily suspend Caelyx pegylated liposomal
treatment in patients when the ANC count is < 1,000/mm3 and/or the platelet count is < 50,000/mm3.
G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC
count is < 1,000/mm3 in subsequent cycles.
Hepatic Impairment
Caelyx pegylated liposomal pharmacokinetics determined in a small number of patients with elevated
total bilirubin levels do not differ from patients with normal total bilirubin; however, until further
experience is gained, the Caelyx pegylated liposomal dosage in patients with impaired hepatic
function should be reduced based on the experience from the breast and ovarian clinical trial programs
as follows: at initiation of therapy, if the bilirubin is between 1.2-3.0 mg/dl, the first dose is reduced by
25%. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50%. If the patient tolerates the first
dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to
the next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle 2; if
reduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can be
increased to full dose for subsequent cycles if tolerated. Caelyx pegylated liposomal can be
administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes
up to 4 x the upper limit of the normal range. Prior to Caelyx pegylated liposomal administration,
evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline
phosphatase, and bilirubin.
Renal Impairment
As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be
required. Population pharmacokinetic data (in the range of creatinine clearance tested of
30-156 ml/min) demonstrate that Caelyx pegylated liposomal clearance is not influenced by renal
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function. No pharmacokinetic data are available in patients with creatinine clearance of less than
30 ml/min.
AIDS-related KS patients with splenectomy

As there is no experience with Caelyx pegylated liposomal in patients who have had splenectomy,
treatment with Caelyx pegylated liposomal is not recommended.
Paediatric population
The experience in children is limited. Caelyx pegylated liposomal is not recommended in patients
below 18 years of age.
Elderly
Population based analysis demonstrates that age across the range tested (21–75 years) does not
significantly alter the pharmacokinetics of Caelyx pegylated liposomal.
Method of administration
Caelyx pegylated liposomal is administered as an intravenous infusion. For further instructions on
preparation and special precautions for handling (see section 6.6).
Do not administer Caelyx pegylated liposomal as a bolus injection or undiluted dispersion. It is

recommended that the Caelyx pegylated liposomal infusion line be connected through the side port of
an intravenous infusion of 5% (50 mg/ml) glucose to achieve further dilution and minimise the risk of
thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with
in-line filters. Caelyx pegylated liposomal must not be given by the intramuscular or subcutaneous
route (see section 6.6).
For doses < 90 mg: dilute Caelyx pegylated liposomal in 250 ml 5% (50 mg/ml) glucose solution for
infusion.
For doses ≥ 90 mg: dilute Caelyx pegylated liposomal in 500 ml 5% (50 mg/ml) glucose solution for
infusion.
Breast cancer/Ovarian cancer/Multiple myeloma

To minimise the risk of infusion reactions, the initial dose is administered at a rate no greater than
1 mg/minute. If no infusion reaction is observed, subsequent Caelyx pegylated liposomal infusions
may be administered over a 60-minute period.
In those patients who experience an infusion reaction, the method of infusion should be modified as
follows:
5% of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction,
the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be
completed over the next hour for a total infusion time of 90 minutes.
AIDS-related KS
The dose of Caelyx pegylated liposomal is diluted in 250 ml 5% (50 mg/ml) glucose solution for
infusion and administered by intravenous infusion over 30 minutes.
4.3 Contraindications
Hypersensitivity to the active substance, peanut or soya, or to any of the excipients listed in section
6.1.
Caelyx pegylated liposomal must not be used to treat AIDS-KS that may be treated effectively with
local therapy or systemic alfa-interferon.
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4.4 Special warnings and precautions for use
Given the difference in pharmacokinetic profiles and dosing schedules, Caelyx pegylated liposomal
should not be used interchangeably with other formulations of doxorubicin hydrochloride.
Cardiac toxicity
It is recommended that all patients receiving Caelyx pegylated liposomal routinely undergo frequent
ECG monitoring. Transient ECG changes such as T-wave flattening, S-T segment depression and
benign arrhythmias are not considered mandatory indications for the suspension of Caelyx pegylated
liposomal therapy. However, reduction of the QRS complex is considered more indicative of cardiac
toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e.,
endomyocardial biopsy, must be considered.
More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are
a measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated
Angiography (MUGA). These methods must be applied routinely before the initiation of Caelyx
pegylated liposomal therapy and repeated periodically during treatment. The evaluation of left
ventricular function is considered to be mandatory before each additional administration of Caelyx
pegylated liposomal that exceeds a lifetime cumulative anthracycline dose of 450 mg/m2.
The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance
during anthracycline therapy are to be employed in the following order: ECG monitoring,
measurement of left ventricular ejection fraction, endomyocardial biopsy. If a test result indicates
possible cardiac injury associated with Caelyx pegylated liposomal therapy, the benefit of continued
therapy must be carefully weighed against the risk of myocardial injury.
In patients with cardiac disease requiring treatment, administer Caelyx pegylated liposomal only when
the benefit outweighs the risk to the patient.
Exercise caution in patients with impaired cardiac function who receive Caelyx pegylated liposomal.
Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction has substantially
decreased relative to pre-treatment values and/or left ventricular ejection fraction is lower than a
prognostically relevant value (e.g., < 45%), endomyocardial biopsy may be considered and the benefit
of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac
damage.
Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and
may also be encountered several weeks after discontinuation of therapy.
Caution must be observed in patients who have received other anthracyclines. The total dose of
doxorubicin hydrochloride must also take into account any previous (or concomitant) therapy with
cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g., 5-fluorouracil. Cardiac
toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m2 in patients with prior
mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.
The cardiac safety profile for the dosing schedule recommended for both breast and ovarian cancer
(50 mg/m2) is similar to the 20 mg/m2 profile in patients with AIDS-KS (see section 4.8).
Myelosuppression
Many patients treated with Caelyx pegylated liposomal have baseline myelosuppression due to such
factors as their pre-existing HIV disease or numerous concomitant or previous medications, or
tumours involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of
50 mg/m2, myelosuppression was generally mild to moderate, reversible, and was not associated with
episodes of neutropaenic infection or sepsis. Moreover, in a controlled clinical trial of Caelyx
pegylated liposomal vs. topotecan, the incidence of treatment related sepsis was substantially less in
the Caelyx pegylated liposomal-treated ovarian cancer patients as compared to the topotecan treatment
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group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer
receiving Caelyx pegylated liposomal in a first-line clinical trial. In contrast to the experience in
patients with breast cancer or ovarian cancer, myelosuppression appears to be the dose-limiting
adverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrow
suppression, periodic blood counts must be performed frequently during the course of Caelyx
pegylated liposomal therapy, and at a minimum, prior to each dose of Caelyx pegylated liposomal.
Persistent severe myelosuppression, may result in superinfection or haemorrhage.
In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen,

opportunistic infections were apparently more frequent during treatment with Caelyx pegylated
liposomal. Patients and doctors must be aware of this higher incidence and take action as appropriate.
Secondary haematological malignancies

As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and
myelodysplasias have been reported in patients having received combined treatment with doxorubicin.
Therefore, any patient treated with doxorubicin should be kept under haematological supervision.
Secondary oral neoplasms

Very rare cases of secondary oral cancer have been reported in patients with long-term (more than one
year) exposure to Caelyx pegylated liposomal or those receiving a cumulative Caelyx pegylated
liposomal dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosed both, during
treatment with Caelyx pegylated liposomal, and up to 6 years after the last dose. Patients should be
examined at regular intervals for the presence of oral ulceration or any oral discomfort that may be
indicative of secondary oral cancer.
Infusion-associated reactions
Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like or
anaphylactoid-like reactions, with symptoms including asthma, flushing, urticarial rash, chest pain,
fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back
pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the
infusion of Caelyx pegylated liposomal. Very rarely, convulsions also have been observed in relation
to infusion reactions. Temporarily stopping the infusion usually resolves these symptoms without
further therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids,
adrenaline, and anticonvulsants), as well as emergency equipment should be available for immediate
use. In most patients treatment can be resumed after all symptoms have resolved, without recurrence.
Infusion reactions rarely recur after the first treatment cycle. To minimise the risk of infusion
reactions, the initial dose should be administered at a rate no greater than 1 mg/minute (see section
4.2).
Palmar plantar erythrodysaesthesia syndrome (PPE)

PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event,
it is generally seen after two or three cycles of treatment. Improvement usually occurs in 1-2 weeks,
and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of
50-150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE,
however, these therapies have not been evaluated in phase III trials. Other strategies to prevent and
treat PPE include keeping hands and feet cool, by exposing them to cool water (soaks, baths, or
swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or
shoes that are tight fitting). PPE appears to be primarily related to the dose schedule and can be
reduced by extending the dose interval 1- 2 weeks (see section 4.2). However, this reaction can be
severe and debilitating in some patients and may require discontinuation of treatment (see section 4.8).
Extravasation
Although local necrosis following extravasation has been reported very rarely, Caelyx pegylated
liposomal is considered to be an irritant. Animal studies indicate that administration of doxorubicin
hydrochloride as a liposomal formulation reduces the potential for extravasation injury. If any signs or
symptoms of extravasation occur (e.g., stinging, erythema) terminate the infusion immediately and
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restart in another vein. The application of ice over the site of extravasation for approximately 30
minutes may be helpful in alleviating the local reaction. Caelyx pegylated liposomal must not be given
by the intramuscular or subcutaneous route.
Diabetic patients
Please note that each vial of Caelyx pegylated liposomal contains sucrose and the dose is administered
in 5% (50 mg/ml) glucose solution for infusion.
Excipients
This medicine contains less than 1 mmol sodium (23 mg) per dose and is essentially ‘sodium-free’.
For common adverse events which required dose modification or discontinuation see section 4.8.
4.5 Interaction with other medicinal products and other forms of interaction
No formal medicinal product interaction studies have been performed with Caelyx pegylated
liposomal, although phase II combination trials with conventional chemotherapy agents have been
conducted in patients with gynaecological malignancies. Exercise caution in the concomitant use of
medicinal products known to interact with standard doxorubicin hydrochloride. Caelyx pegylated
liposomal, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other
anti-cancer therapies. During clinical trials in patients with solid tumours (including breast and ovarian
cancer) who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were
noted. In patients with AIDS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and
enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with standard doxorubicin
hydrochloride. Caution must be exercised when giving any other cytotoxic agents, especially
myelotoxic agents, at the same time.
4.6 Fertility, pregnancy and lactation
Pregnancy
Doxorubicin hydrochloride is suspected to cause serious birth defects when administered during
pregnancy. Therefore, Caelyx pegylated liposomal should not be used during pregnancy unless clearly
necessary.
Women of child-bearing potential

Women of child-bearing potential must be advised to avoid pregnancy while they or their male partner
are receiving Caelyx pegylated liposomal and in the six months following discontinuation of Caelyx
pegylated liposomal therapy (see section 5.3).
Breast-feeding
It is not known whether Caelyx pegylated liposomal is excreted in human milk. Because many
medicinal products, including anthracyclines, are excreted in human milk, and because of the potential
for serious adverse reactions in nursing infants, therefore mothers must discontinue nursing prior to
beginning Caelyx pegylated liposomal treatment. Health experts recommend that HIV infected women
do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Fertility
The effect of doxorubicin hydrochloride on human fertility has not been evaluated (see section 5.3).
4.7 Effects on ability to drive and use machines
Caelyx pegylated liposomal has no or negligible influence on the ability to drive and use machines.
However, in clinical studies to date, dizziness and somnolence were associated infrequently (< 5%)
with the administration of Caelyx pegylated liposomal. Patients who suffer from these effects must
avoid driving and operating machinery.
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4.8 Undesirable effects
Summary of the safety profile

The most frequent adverse reactions (≥ 20%) were neutropaenia, nausea, leukopaenia, anaemia, and
fatigue.
Severe adverse reactions (Grade 3/4 adverse reactions occurring in ≥ 2% of patients) were
neutropaenia, PPE, leukopaenia, lymphopaenia, anaemia, thrombocytopaenia, stomatitis, fatigue,
diarrhoea, vomiting, nausea, pyrexia, dyspnoea, and pneumonia. Less frequently reported severe
adverse reactions included Pneumocystis jirovecii pneumonia, abdominal pain, cytomegalovirus
infection including cytomegalovirus chorioretinitis, asthenia, cardiac arrest, cardiac failure, cardiac
failure congestive, pulmonary embolism, thrombophlebitis, venous thrombosis, anaphylactic reaction,
anaphylactoid reaction, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
Tabulated list of adverse reactions

Table 5 summarises the adverse drug reactions that occurred in patients receiving Caelyx pegylated
liposomal in 4,231 patients for the treatment of breast cancer, ovarian cancer, multiple myeloma, and
AIDS-related KS. Post-marketing adverse reactions are also included, as indicated by “b”. Frequencies
are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100),
rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (frequency cannot be estimated
from the available data). Within each frequency grouping, where relevant, adverse reactions are
presented in order of decreasing seriousness.
Table 5: Adverse reactions in patients treated with Caelyx pegylated liposomal

System Organ Frequency All Grades Adverse Drug Reaction
Class
Infections and Common Sepsis
infestations Pneumonia
Pneumocystis jirovecii pneumonia
Cytomegalovirus infection including
cytomegalovirus chorioretinitis
Mycobacterium avium complex infection
Candidiasis
Herpes zoster
Urinary tract infection
Infection
Upper respiratory tract infection
Oral candidiasis
Folliculitis
Pharyngitis
Nasopharyngitis
Uncommon Herpes simplex
Fungal infection
Rare Opportunistic infection (including Aspergillus,
Histoplasma, Isospora, Legionella,
Microsporidium, Salmonella, Staphylococcus,
Toxoplasma, Tuberculosis)a
Neoplasms Not known Acute myeloid leukaemiab
benign, Myelodysplastic syndromeb
malignant and Oral neoplasmb
unspecified
(including cysts
and polyps)
Blood and Very common Leukopaenia
lymphatic system Neutropaenia
10
disorders Lymphopaenia
Anaemia (including hypochromic)
Common Thrombocytopaenia
Febrile neutropaenia
Uncommon Pancytopaenia
Thrombocytosis
Rare Bone marrow failure
Immune system Uncommon Hypersensitivity
disorders Anaphylactic reaction
Rare Anaphylactoid reaction
Metabolism and Very common Decreased appetite
nutrition Common Cachexia
disorders Dehydration
Hypokalaemia
Hyponatraemia
Hypocalcaemia
Uncommon Hyperkalaemia
Hypomagnesaemia
Psychiatric Common Confusional state
disorders Anxiety
Depression
Insomnia
Nervous system Common Neuropathy peripheral
disorders Peripheral sensory neuropathy
Neuralgia
Paraesthesia
Hypoaesthesia
Dysgeusia
Headache
Lethargy
Dizziness
Uncommon Polyneuropathy
Convulsion
Syncope
Dysaesthesia
Somnolence
Eye disorders Common Conjunctivitis
Uncommon Vision blurred
Lacrimation increased
Rare Retinitis
Cardiac Common Tachycardia
disordersa Uncommon Palpitations
Cardiac arrest
Cardiac failure
Cardiac failure congestive
Cardiomyopathy
Cardiotoxicity
Rare Ventricular arrhythmia
Bundle branch block right
Conduction disorder
Atrioventricular block
Cyanosis
Vascular Common Hypertension
disorders Hypotension
11
Flushing
Uncommon Pulmonary embolism
Infusion site necrosis (including soft tissue
necrosis and skin necrosis)
Phlebitis
Orthostatic hypotension
Rare Thrombophlebitis
Venous thrombosis
Vasodilatation
Respiratory, Common Dyspnoea
thoracic and Dyspnoea exertional
mediastinal Epistaxis
disorders Cough
Uncommon Asthma
Chest discomfort
Rare Throat tightness
Gastrointestinal Very common Stomatitis
disorders Nausea
Vomiting
Diarrhoea
Constipation
Common Gastritis
Aphthous stomatitis
Mouth ulceration
Dyspepsia
Dysphagia
Oesophagitis
Abdominal pain
Abdominal pain upper
Oral pain
Dry mouth
Uncommon Flatulence
Gingivitis
Rare Glossitis
Lip ulceration
Skin and Very common Palmar plantar erythrodysaesthesia syndromea
subcutaneous Rash (including erythematous, maculo-papular,
tissue disorders and papular)
Alopecia
Common Skin exfoliation
Blister
Dry skin
Erythema
Pruritus
Hyperhidrosis
Skin hyperpigmentation
Uncommon Dermatitis
Dermatitis exfoliative
Acne
Skin ulcer
Dermatitis allergic
Urticaria
Skin discolouration
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Petechiae
Pigmentation disorder
Nail disorder
Rare Toxic epidermal necrolysis
Erythema multiforme
Dermatitis bullous
Lichenoid keratosis
Not known Stevens-Johnson syndromeb
Musculoskeletal Very common Musculoskeletal pain (including musculoskeletal
and connective chest pain, back pain, pain in extremity)
tissue disorders Common Muscle spasms
Myalgia
Arthralgia
Bone pain
Uncommon Muscular weakness
Renal and Common Dysuria
urinary disorders
Reproductive Uncommon Breast pain
disorders
Rare Vaginal infection
Scrotal erythema
General Very common Pyrexia
disorders and Fatigue
administration Common Infusion-related reaction
site conditions Pain
Chest pain
Influenza-like illness
Chills
Mucosal inflammation
Asthenia
Malaise
Oedema
Oedema peripheral
Uncommon Administration site extravasation
Injection site reaction
Face oedema
Hyperthermia
Rare Mucous membrane disorder
Investigations Common Weight decreased
Uncommon Ejection fraction decreased
Rare Liver function test abnormal (including Blood
bilirubin increased, Alanine aminotransferase
increased and Aspartate aminotransferase
increased)
Blood creatinine increased
Injury, poisoning Uncommon Radiation recall phenomenona
and procedural
complications
a
See Description of selected adverse reactions
b
Post-marketing adverse reaction
Description of selected adverse reactions

Palmar plantar erythrodysaesthesia
The most common undesirable effect reported in breast/ovarian clinical trials was palmar-plantar
erythrodysesthesia (PPE). The overall incidence of PPE reported was 41.3% and 51.1% in the ovarian
13
and breast clinical trials, respectively. These effects were mostly mild, with severe (grade 3) cases
reported in 16.3% and 19.6% of patients. The reported incidence of life-threatening (grade 4) cases
was < 1%. PPE infrequently resulted in permanent treatment discontinuation (1.9% and 10.8%). PPE
was reported in 16% of multiple myeloma patients treated with Caelyx pegylated liposomal plus
bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was
reported. The rate of PPE was substantially lower in the AIDS-KS population (1.3% all grade, 0.4%
grade 3 PPE, no grade 4 PPE). See section 4.4.
Opportunistic infections
Respiratory undesirable effects commonly occurred in clinical studies of Caelyx pegylated liposomal
and may be related to opportunistic infections (OI’s) in the AIDS population. Opportunistic infections
are observed in KS patients after administration with Caelyx pegylated liposomal, and are frequently
observed in patients with HIV induced immunodeficiency. The most frequently observed OI’s in
clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis jirovecii pneumonia,
and mycobacterium avium complex.
Cardiac toxicity
An increased incidence of congestive heart failure is associated with doxorubicin therapy at
cumulative lifetime doses > 450 mg/m2 or at lower doses for patients with cardiac risk factors.
Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of Caelyx
pegylated liposomal greater than 460 mg/m2 indicate no evidence of anthracycline-induced
cardiomyopathy. The recommended dose of Caelyx pegylated liposomal for AIDS-KS patients is
20 mg/m2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a
concern for these AIDS-KS patients (> 400 mg/m2) would require more than 20 courses of Caelyx
pegylated liposomal therapy over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative
anthracycline doses of 509 mg/m2–1,680 mg/m2. The range of Billingham cardiotoxicity scores was
grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.
In the pivotal phase III trial versus doxorubicin, 58/509 (11.4%) randomised subjects (10 treated with
Caelyx pegylated liposomal at a dose of 50 mg/m2/every 4 weeks versus 48 treated with doxorubicin
at a dose of 60 mg/m2/every 3 weeks) met the protocol-defined criteria for cardiac toxicity during
treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater from
baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the
LVEF became abnormal (less than the lower limit for normal). None of the 10 Caelyx pegylated
liposomal subjects who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF.
In contrast, 10 of 48 doxorubicin subjects who had cardiac toxicity by LVEF criteria also developed
signs and symptoms of CHF.
In patients with solid tumours, including a subset of patients with breast and ovarian cancers, treated at
a dose of 50 mg/m2/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m2, the
incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with
Caelyx pegylated liposomal 50 mg/m2/cycle, and having a baseline measurement of left ventricular
ejection fraction (LVEF) and at least one follow-up measurement assessed by MUGA scan,
88 patients had a cumulative anthracycline dose of > 400 mg/m2, an exposure level associated with an
increased risk of cardiovascular toxicity with conventional doxorubicin. Only 13 of these 88 patients
(15%) had at least one clinically significant change in their LVEF, defined as an LVEF value less than
45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulative
anthracycline dose of 944 mg/m2), discontinued study treatment because of clinical symptoms of
congestive heart failure.
Radiation recall phenomenon

Recall of skin reaction due to prior radiotherapy has occurred uncommonly with Caelyx pegylated
liposomal administration.
14
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.
4.9 Overdose
Acute overdosing with doxorubicin hydrochloride worsens the toxic effects of mucositis, leukopaenia
and thrombocytopaenia. Treatment of acute overdose of the severely myelosuppressed patient consists
of hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of
mucositis.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code:
L01DB01.
Mechanism of action
The active ingredient of Caelyx pegylated liposomal is doxorubicin hydrochloride, a cytotoxic
anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of
the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA,
RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the
result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus
preventing their unwinding for replication.
Clinical efficacy and safety

A phase III randomised study of Caelyx pegylated liposomal versus doxorubicin in patients with
metastatic breast cancer was completed in 509 patients. The protocol-specified objective of
demonstrating non-inferiority between Caelyx pegylated liposomal and doxorubicin was met, the
hazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% CI for HR=0.82-1.22). The
treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT
population.
The primary analysis of cardiac toxicity showed the risk of developing a cardiac event as a function of
cumulative anthracycline dose was significantly lower with Caelyx pegylated liposomal than with
doxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m2 there were no cardiac
events with Caelyx pegylated liposomal.
A phase III comparative study of Caelyx pegylated liposomal versus topotecan in patients with
epithelial ovarian cancer following the failure of first-line, platinum-based chemotherapy was
completed in 474 patients. There was a benefit in overall survival (OS) for Caelyx pegylated
liposomal-treated patients over topotecan-treated patients as indicated by a hazard ratio (HR) of 1.216
(95% CI: 1.000; 1.478), p=0.050. The survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2%
respectively on Caelyx pegylated liposomal, compared to 54.0%, 23.6% and 13.2% on topotecan.
For the sub-group of patients with platinum-sensitive disease the difference was greater: HR of 1.432
The treatments were similar in the sub-group of patients with platinum-refractory disease: HR of 1.069
15
A phase III randomised, parallel-group, open-label, multicentre study comparing the safety and
efficacy of Caelyx pegylated liposomal plus bortezomib combination therapy with bortezomib
monotherapy in patients with multiple myeloma who have received at least 1 prior therapy and who
did not progress while receiving anthracycline-based therapy, was conducted in 646 patients. There
was a significant improvement in the primary endpoint of time to progression (TTP) for patients
treated with combination therapy of Caelyx pegylated liposomal plus bortezomib compared to patients
treated with bortezomib monotherapy as indicated by a risk reduction (RR) of 35% (95% CI: 21-47%),
p < 0.0001, based on 407 TTP events. The median TTP was 6.9 months for the bortezomib
monotherapy patients compared with 8.9 months for the Caelyx pegylated liposomal plus bortezomib
combination therapy patients. A protocol-defined interim analysis (based on 249 TTP events)
triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of
45% (95% CI: 29-57%), p < 0.0001. The median TTP was 6.5 months for the bortezomib
monotherapy patients compared with 9.3 months for the Caelyx pegylated liposomal plus bortezomib
combination therapy patients. These results, though not mature, constituted the protocol defined final
analysis. The final analysis for overall survival (OS) performed after a median follow-up of 8.6 years
showed no significant difference in OS between the two treatment arms. The median OS was
30.8 months (95% CI; 25.2-36.5 months) for the bortezomib monotherapy patients and 33.0 months
(95% CI; 28.9-37.1 months) for the Caelyx pegylated liposomal plus bortezomib combination therapy
patients.
5.2 Pharmacokinetic properties
Caelyx pegylated liposomal is a long-circulating pegylated liposomal formulation of doxorubicin

hydrochloride. Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer
methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface
creating a protective coating that reduces interactions between the lipid bilayer membrane and the
plasma components. This allows the Caelyx pegylated liposomal liposomes to circulate for prolonged
periods in the blood stream. Pegylated liposomes are small enough (average diameter of
approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumours.
Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation
in tumours has been seen in mice with C-26 colon carcinoma tumours and in transgenic mice with
KS-like lesions. The pegylated liposomes also have a low permeability lipid matrix and internal
aqueous buffer system that combine to keep doxorubicin hydrochloride encapsulated during liposome
residence time in circulation.
The plasma pharmacokinetics of Caelyx pegylated liposomal in humans differ significantly from those
reported in the literature for standard doxorubicin hydrochloride preparations. At lower doses
(10 mg/m2–20 mg/m2) Caelyx pegylated liposomal displayed linear pharmacokinetics. Over the dose
range of 10 mg/m2–60 mg/m2 Caelyx pegylated liposomal displayed non-linear pharmacokinetics.
Standard doxorubicin hydrochloride displays extensive tissue distribution (volume of distribution: 700
to 1,100 l/m2) and a rapid elimination clearance (24 to 73 l/h/m2). In contrast, the pharmacokinetic
profile of Caelyx pegylated liposomal indicates that Caelyx pegylated liposomal is confined mostly to
the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the
liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the
tissue compartment.
At equivalent doses, the plasma concentration and AUC values of Caelyx pegylated liposomal which
represent mostly pegylated liposomal doxorubicin hydrochloride (containing 90% to 95% of the
measured doxorubicin) are significantly higher than those achieved with standard doxorubicin
hydrochloride preparations.
Caelyx pegylated liposomal should not be used interchangeably with other formulations of
doxorubicin hydrochloride.
16
Population pharmacokinetics
The pharmacokinetics of Caelyx pegylated liposomal was evaluated in 120 patients from 10 different
clinical trials using the population pharmacokinetic approach. The pharmacokinetics of Caelyx
pegylated liposomal over the dose range of 10 mg/m2 to 60 mg/m2 was best described by a two
compartment non-linear model with zero order input and Michaelis-Menten elimination. The mean
intrinsic clearance of Caelyx pegylated liposomal was 0.030 l/h/m2 (range 0.008 to 0.152 l/h/m2) and
the mean central volume of distribution was 1.93 l/m2 (range 0.96-3.85 l/m2) approximating the plasma
volume. The apparent half-life ranged from 24-231 hours, with a mean of 73.9 hours.
Breast cancer patients

The pharmacokinetics of Caelyx pegylated liposomal determined in 18 patients with breast carcinoma
were similar to the pharmacokinetics determined in the larger population of 120 patients with various
cancers. The mean intrinsic clearance was 0.016 l/h/m2 (range 0.008-0.027 l/h/m2), the mean central
volume of distribution was 1.46 l/m2 (range 1.10-1.64 l/m2). The mean apparent half-life was
71.5 hours (range 45.2-98.5 hours).
Ovarian cancer patients

The pharmacokinetics of Caelyx pegylated liposomal determined in 11 patients with ovarian
carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients
with various cancers. The mean intrinsic clearance was 0.021 l/h/m2 (range 0.009–0.041 l/h/m2), the
mean central volume of distribution was 1.95 l/m2 (range 1.67–2.40 l/m2). The mean apparent half-life
was 75.0 hours (range 36.1–125 hours).
AIDS-related KS patients
The plasma pharmacokinetics of Caelyx pegylated liposomal were evaluated in 23 patients with KS
who received single doses of 20 mg/m2 administered by a 30-minute infusion. The pharmacokinetic
parameters of Caelyx pegylated liposomal (primarily representing pegylated liposomal doxorubicin
hydrochloride and low levels of unencapsulated doxorubicin hydrochloride) observed after the
20 mg/m2 doses are presented in Table 6.
Table 6. Pharmacokinetic parameters in Caelyx pegylated liposomal-treated AIDS-KS

patients
Mean + standard error
Parameter 20 mg/m2 (n=23)
Maximum plasma concentration* (µg/ml) 8.34 ± 0.49
Plasma clearance (l/h/m2) 0.041 ± 0.004
Volume of distribution (l/m2) 2.72 ± 0.120
AUC (µg/ml⋅h) 590.00 ± 58.7
λ1 half-life (hours) 5.2 ± 1.4
λ2 half-life (hours) 55.0 ± 4.8
* Measured at the end of a 30-minute infusion
5.3 Preclinical safety data
In repeat dose studies conducted in animals, the toxicity profile of Caelyx pegylated liposomal appears
very similar to that reported in humans who receive long-term infusions of standard doxorubicin
hydrochloride. With Caelyx pegylated liposomal, the encapsulation of doxorubicin hydrochloride in
pegylated liposomes results in these effects having a differing strength, as follows.
Cardiotoxicity
Studies in rabbits have shown that the cardiotoxicity of Caelyx pegylated liposomal is reduced
compared with conventional doxorubicin hydrochloride preparations.
Dermal toxicity
In studies performed after the repeated administration of Caelyx pegylated liposomal to rats and dogs,
serious dermal inflammations and ulcer formations were observed at clinically relevant dosages. In the
17
study in dogs, the occurrence and severity of these lesions was reduced by lowering the dose or
prolonging the intervals between doses. Similar dermal lesions, which are described as palmar-plantar
erythrodysesthesia were also observed in patients after long-term intravenous infusion (see section
4.8).
Anaphylactoid response
During repeat dose toxicology studies in dogs, an acute response characterised by hypotension, pale
mucous membranes, salivation, emesis and periods of hyperactivity followed by hypoactivity and
lethargy was observed following administration of pegylated liposomes (placebo). A similar, but less
severe response was also noted in dogs treated with Caelyx pegylated liposomal and standard
doxorubicin.
The hypotensive response was reduced in magnitude by pretreatment with antihistamines. However,
the response was not life-threatening and the dogs recovered quickly upon discontinuation of
treatment.
Local toxicity
Subcutaneous tolerance studies indicate that Caelyx pegylated liposomal, as against standard
doxorubicin hydrochloride, causes slighter local irritation or damage to the tissue after a possible
extravasation.
Mutagenicity and carcinogenicity

Although no studies have been conducted with Caelyx pegylated liposomal, doxorubicin
hydrochloride, the pharmacologically active ingredient of Caelyx pegylated liposomal, is mutagenic
and carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.
Reproductive toxicity
Caelyx pegylated liposomal resulted in mild to moderate ovarian and testicular atrophy in mice after a
single dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in rats after
repeat doses ≥ 0.25 mg/kg/day and diffuse degeneration of the seminiferous tubules and a marked
decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (see section 4.6).
Nephrotoxicity
A study has shown that Caelyx pegylated liposomal at a single intravenous dose of over twice the
clinical dose produces renal toxicity in monkeys. Renal toxicity has been observed with even lower
single doses of doxorubicin HCl in rats and rabbits. Since an evaluation of the post-marketing safety
database for Caelyx pegylated liposomal in patients has not suggested a significant nephrotoxicity
liability of Caelyx pegylated liposomal, these findings in monkeys may not have relevance to patient
risk assessment.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
α-(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ω-methoxypoly(oxyethylen)-40
sodium salt (MPEG-DSPE)
fully hydrogenated soy phosphatidylcholine (HSPC)
cholesterol
ammonium sulphate
sucrose
histidine
water for injections
hydrochloric acid (for pH-adjustment)
sodium hydroxide (for pH-adjustment)
18
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
20 months.
After dilution:
- Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.
- From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user
and should not be longer than 24 hours at 2°C to 8°C.
- Partially used vials must be discarded.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).

Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Type I glass vials, each with a siliconised grey bromobutyl stopper, and an aluminium seal, with a
deliverable volume of 10 ml (20 mg) or 25 ml (50 mg).
Caelyx pegylated liposomal is supplied as a single pack or packs of ten vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Do not use material that shows evidence of precipitation or any other particulate matter.
Caution must be exercised in handling Caelyx pegylated liposomal dispersion. The use of gloves is
required. If Caelyx pegylated liposomal comes into contact with skin or mucosa, wash immediately
and thoroughly with soap and water. Caelyx pegylated liposomal must be handled and disposed of in a
manner consistent with that of other anticancer medicinal products in accordance with local
requirements.
Determine the dose of Caelyx pegylated liposomal to be administered (based upon the recommended
dose and the patient’s body surface area). Take the appropriate volume of Caelyx pegylated liposomal
up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or
bacteriostatic agent is present in Caelyx pegylated liposomal. The appropriate dose of Caelyx
pegylated liposomal must be diluted in 5% (50 mg/ml) glucose solution for infusion prior to
administration. For doses < 90 mg, dilute Caelyx pegylated liposomal in 250 ml, and for doses
≥ 90 mg, dilute Caelyx pegylated liposomal in 500 ml. This can be infused over 60 or 90 minutes as
detailed in 4.2.
The use of any diluent other than 5% (50 mg/ml) glucose solution for infusion, or the presence of any
bacteriostatic agent such as benzyl alcohol may cause precipitation of Caelyx pegylated liposomal.
It is recommended that the Caelyx pegylated liposomal infusion line be connected through the side
port of an intravenous infusion of 5% (50 mg/ml) glucose. Infusion may be given through a peripheral
vein. Do not use with in-line filters.
19
7. MARKETING AUTHORISATION HOLDER
Baxter Holding B.V.

Kobaltweg 49,
3542 CE Utrecht,
Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/96/011/001
EU/1/96/011/002
EU/1/96/011/003
EU/1/96/011/004
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 21 June 1996

Date of lastest renewal: 19 May 2006
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.ema.europa.eu/.
20
ANNEX II
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND

USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE

AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
21
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer responsible for batch release
Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION
• Periodic safety update reports (PSURs)
The requirements for submission of PSURs for this medicinal product are set out in the list of Union
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any
subsequent updates published on the European medicines web-portal.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT
• Risk management plan (RMP)
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities
and interventions detailed in the RMP presented in Module 1.8.2. of the marketing authorisation and
any agreed subsequent updates of the RMP.
An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.
22
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CAELYX PEGYLATED LIPOSOMAL CARTON 20 mg/10 ml – 1 vial

CAELYX PEGYLATED LIPOSOMAL CARTON 20 mg/10 ml – 10 vials

doxorubicin hydrochloride
2. STATEMENT OF ACTIVE SUBSTANCE(S)
One ml of Caelyx pegylated liposomal contains 2 mg doxorubicin hydrochloride.
3. LIST OF EXCIPIENTS
Excipients: α-(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ϖ-
methoxypoly(oxyethylen)-40 sodium salt, fully hydrogenated soy phosphatidylcholine, cholesterol,
ammonium sulphate, sucrose, histidine, water for injections, hydrochloric acid and sodium hydroxide.
4. PHARMACEUTICAL FORM AND CONTENTS
1 vial
10 vials
20 mg/10 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use after dilution.

Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use interchangeably with other formulations of doxorubicin hydrochloride.
8. EXPIRY DATE
EXP
25
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cytotoxic
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Baxter Holding B.V.

Kobaltweg 49,
3542 CE Utrecht,
Netherlands
EU/1/96/011/001 (1 vial)
EU/1/96/011/002 (10 vials)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CAELYX PEGYLATED LIPOSOMAL CARTON 50 mg/25 ml – 1 vial

CAELYX PEGYLATED LIPOSOMAL CARTON 50 mg/25 ml – 10 vials

2. STATEMENT OF ACTIVE SUBSTANCE(S)
One ml of Caelyx pegylated liposomal contains 2 mg doxorubicin hydrochloride.
3. LIST OF EXCIPIENTS
Excipients: α-(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ϖ-
methoxypoly(oxyethylen)-40 sodium salt, fully hydrogenated soy phosphatidylcholine, cholesterol,
ammonium sulphate, sucrose, histidine, water for injections, hydrochloric acid and sodium hydroxide.
4. PHARMACEUTICAL FORM AND CONTENTS
1 vial
10 vials
50 mg/25 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use after dilution.

Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Do not use interchangeably with other formulations of doxorubicin hydrochloride.
8. EXPIRY DATE
EXP
27
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cytotoxic
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Baxter Holding B.V.

Kobaltweg 49,
3542 CE Utrecht,
Netherlands
EU/1/96/011/003 (1 vial)
EU/1/96/011/004 (10 vials)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
CAELYX PEGYLATED LIPOSOMAL LABEL 20 mg/10 ml
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
Caelyx pegylated liposomal 2 mg/ml sterile concentrate

IV after dilution.
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Batch
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
20 mg/10 ml
6. OTHER
29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
CAELYX PEGYLATED LIPOSOMAL LABEL 50 mg/25 ml
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
Caelyx pegylated liposomal 2 mg/ml sterile concentrate

IV after dilution.
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Batch
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
50 mg/25 ml
6. OTHER
30
B. PACKAGE LEAFLET
31
Package leaflet: information for the user

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.
What is in this leaflet

1. What Caelyx pegylated liposomal is and what it is used for
2. What you need to know before you use 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 antitumour agent.
Caelyx pegylated liposomal is used to treat cancer of the breast in patients at risk for heart problems.
Caelyx pegylated liposomal is also used to treat cancer of the ovary. It is used to kill cancer cells,
shrink the size of the tumour, delay the growth of the tumour, and extend your survival.
Caelyx pegylated liposomal is also used in combination with another medicine, bortezomib, to treat
multiple myeloma (a cancer of the blood) in patients who have received at least 1 prior therapy.
Caelyx pegylated liposomal is also used to produce an improvement in your Kaposi’s sarcoma
including flattening, lightening and even shrinkage of the cancer. Other symptoms of Kaposi’s
sarcoma, such as swelling around the tumour, may also improve or disappear.
Caelyx pegylated liposomal contains a medicine which is able to interact with cells in such a way as to
selectively kill cancer cells. The doxorubicin hydrochloride in Caelyx pegylated liposomal is enclosed
in tiny spheres called pegylated liposomes which help to deliver the medicinal product from the blood
stream to the cancerous tissue rather than healthy normal tissue.
2. What you need to know before you use Caelyx pegylated liposomal
Do not use Caelyx pegylated liposomal

- if you are allergic to doxorubicin hydrochloride, peanut or soya, or any of the ingredients of this
medicine (listed in section 6).
Warnings and precautions

You should tell your doctor about any of the following:
- if you are receiving any treatment for heart disease or liver disease;
- if you are diabetic, because Caelyx pegylated liposomal contains sugar which may require an
adjustment to the treatment of your diabetes;
- if you have Kaposi’s sarcoma and have had your spleen removed;
- if you notice sores, discolouration or any discomfort in your mouth.
32
Children and adolescents
Caelyx pegylated liposomal should not be used in children and adolescents, because it is not known
how the medicine will affect them.
Other medicines and Caelyx pegylated liposomal

Tell your doctor or pharmacist
- if you are taking or have recently taken any other medicines, including medicines obtained
without a prescription;
- about any other cancer treatments you are on or have been taking, as particular care needs to be
taken with treatments which reduce the number of white blood cells, as this may cause further
reduction in the number of white blood cells. If you are unsure about what treatments you have
received or any illnesses you have had, discuss these with your doctor.
Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.
Because the active ingredient doxorubicin hydrochloride in Caelyx pegylated liposomal may cause
birth defects, it is important to tell your doctor if you think you are pregnant. Avoid becoming
pregnant while you or your partner are taking Caelyx pegylated liposomal and in the six months
following discontinuation of Caelyx pegylated liposomal treatment.
Because doxorubicin hydrochloride may be harmful to nursing infants, women must discontinue
breast-feeding before starting treatment with Caelyx pegylated liposomal. Health experts recommend
that HIV infected women do not breast-feed their infants under any circumstances in order to avoid
transmission of HIV.
Driving and using machines

Do not drive or use any tools or machines if you feel tired or sleepy from treatment with Caelyx
pegylated liposomal.
Caelyx pegylated liposomal contains soya oil and sodium

Caelyx pegylated liposomal contains soya oil. If you are allergic to peanut or soya, do not use this
medicine.
Caelyx pegylated liposomal contains less than 1 mmol sodium (23 mg) per dose, that is to say
‘essentially sodium-free’.
3. How to use 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 cancer 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
weight). The dose is repeated every 4 weeks for as long as the disease does not progress and you are
able to tolerate the treatment.
If you are being treated for multiple myeloma, and have already received at least 1 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 weight) as a 1 hour intravenous infusion on day 4 of the
bortezomib 3 week regimen immediately after the bortezomib infusion. The dose is repeated as long as
you respond satisfactorily and tolerate treatment.
If you are being treated for Kaposi’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 weight). The dose
33
is repeated every 2 to 3 weeks for 2-3 months, then as often as necessary to maintain an improvement
in your condition.
How Caelyx pegylated liposomal is given

Caelyx pegylated liposomal will be given to you by your doctor in a drip (infusion) into a vein.
Depending on the dose and indication, this may take from 30 minutes to more than one hour (i.e.,
90 minutes).
If you use more Caelyx pegylated liposomal than you should

Acute overdosing worsens side effects like sores in the mouth or decreases the number of white blood
cells and platelets in the blood. Treatment will include administration of antibiotics, platelet cell
transfusions, use of factors which stimulate production of white blood cells and symptomatic treatment
of mouth sores.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
During the infusion of Caelyx pegylated liposomal, the following reactions may occur:
- severe allergic reaction that may include a swollen face, lips, mouth, tongue or throat; difficulty
swallowing or breathing; itchy rash (hives)
- inflamed and narrowed airways in the lungs, causing coughing, wheezing and shortness of
breath (asthma)
- flushing, sweating, chills or a fever
- chest pain or discomfort
- back pain
- high or low blood pressure
- fast heart beat
- fits (seizures)
Leaking of the injection fluid from the veins into the tissues under the skin may occur. If the drip
stings or hurts while you are receiving a dose of Caelyx pegylated liposomal, tell your doctor
immediately.
Your doctor should be contacted immediately if any of the following serious side effects are noticed:
- you develop fever, feel tired, or if you have signs of bruising or bleeding (very common)
- redness, swelling, peeling or tenderness, mainly on the hands or feet (‘hand-foot’ syndrome).
These effects have been seen very commonly and are sometimes severe. In severe cases, these
effects may interfere with certain daily activities, and may last for 4 weeks or longer before
resolving completely. The doctor may wish to delay the start and/or reduce the dose of the next
treatment (see Strategies to prevent and treat hand foot syndrome, below)
- sores in mouth, severe diarrhoea or vomiting or nausea (very common)
- infections (common), including lung infections (pneumonia) or infections that may affect your
vision
- being short of breath (common)
- severe stomach pain (common)
- severe weakness (common)
- severe allergic reaction that may include a swollen face, lips, mouth, tongue or throat; difficulty
swallowing or breathing; itchy rash (hives) (uncommon)
- cardiac arrest (heart stops beating); heart failure, in which the heart does not pump enough
blood to the rest of the body, which makes you short of breath and may lead to swollen legs
(uncommon)
34
- blood clot that moves to the lungs, causes chest pain and makes you short of breath
(uncommon)
- swelling, warmth, or tenderness in the soft tissues of your leg, sometimes with pain which gets
worse when you stand or walk (rare)
- severe or life-threatening rash with blisters and peeling skin, particularly around the mouth,
nose, eyes and genitals (Stevens-Johnson syndrome) or over 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 people)

- decrease in the number of white blood cells, which can increase the chances of infections. In
rare cases, having low white blood cells may lead to severe infection. Anaemia (reduction in red
blood cells) may cause tiredness, and decreased platelets in the blood may increase the risk of
bleeding. It is because of the potential changes in your blood cells that you will have regular
blood tests.
- decreased appetite;
- constipation;
- skin rashes, including redness of the skin, allergic skin rash, red or raised rash on the skin
- hair loss
- pain including in the muscles and chest muscle, joint, arm, or leg
- feeling very tired
Common side effects (may affect up to 1 in 10 people)

- infections, including severe infection throughout the body (sepsis), lung infections, herpes
zoster virus infections (shingles), a type of bacterial infection (mycobacterium avium complex
infection), urinary tract infection, fungal infections (including thrush and oral thrush in the
mouth) infection of the hair roots, infected or irritated throat, infected nose, sinuses or throat
(cold)
- low number of a type of white blood cell (neutrophils), with a fever
- severe weight loss and muscle wasting, not enough water in the body (dehydration), low level of
potassium, sodium, or calcium in the blood
- feeling confused, feeling anxious, depression, difficulty sleeping
- nerve damage that may cause tingling, numbness, pain or loss of pain sensation, nerve pain,
unusual feeling in the skin (such as tingling or a crawling feeling), decreased feeling or
sensitivity, especially in the skin
- change in sense of taste, headache, feeling very sleepy with low energy, feeling dizzy;
- inflamed eyes (conjunctivitis)
- fast heart beat
- high or low blood pressure, flushing
- shortness of breath that may be brought on by physical activity, nose bleeds, cough
- inflamed stomach lining or foodpipe, ulcers (sores) in the mouth, indigestion, difficulty
swallowing, mouth pain, dry mouth
- skin problems, including flaky or dry skin, redness of the skin, blister or ulcer (sore) on the skin,
itching, dark skin patches
- excessive sweating
- muscle spasms or aches
- pain including in the muscles, bone, or back
- pain when passing urine
- allergic reaction to infusion of the medicine, flu-like illness, chills, inflamed lining of the
cavities and passages in the body, such as the nose, mouth or windpipe, feeling weak, generally
feeling unwell, swelling caused by fluid build up in the body, swollen hands, ankles or feet
- weight loss
When Caelyx pegylated liposomal is used alone, some of these effects are less likely to occur, and
some have not occurred at all.
35
Uncommon side effects (may affect up to 1 in 100 people)
- 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 area of the body
- fits (seizures), fainting
- unpleasant or painful sensation, especially to touch, feeling sleepy
- blurred vision, watery eyes
- heart beat feels fast or uneven (palpitations), heart muscle disease, heart damage
- tissue damage (necrosis) where the injection is given, inflamed veins that cause swelling and
pain, feeling dizzy upon sitting up or standing up
- chest discomfort
- passing wind, inflamed gums (gingivitis)
- skin problems or rashes, including flaky or peeling skin, allergic skin rash, ulcer (sore) or hives
on the skin, discoloured skin, change in the natural colour (pigment) of the skin, small red or
purple spots caused by bleeding under the skin, nail problems, acne
- muscle weakness
- breast pain
- irritation or pain where the injection is given
- swollen face, high body temperature
- symptoms (such as inflammation, redness or pain) come back at a part of the body that
previously received radiation therapy or was previously damaged by a chemotherapy injection
into a vein
Rare side effects (may affect up to 1 in 1,000 people)

- infection that occurs in people with a weak immune system
- low number of blood cells made in the bone marrow
- inflamed retina, which may cause changes in vision or blindness
- abnormal heart rhythm, abnormal heart tracing on an ECG (electrocardiogram) and may be with
a slow heart beat, problem with the heart that affects the heart beat and rhythm, blue colour to
the skin and mucosa caused by low oxygen in the blood
- widening of blood vessels
- tight feeling in the throat
- sore and swollen tongue, ulcer (sore) on the lip
- skin rash with fluid-filled blisters
- vaginal infection, redness of the scrotum
- problems with the lining of the cavities and passages in the body, such as the nose, mouth or
windpipe
- abnormal liver blood test results, increased level of ‘creatinine’ in the blood
Not known (frequency cannot be estimated from the available data)

- cancer of the blood that develops quickly and affects the blood cells (acute myeloid leukaemia),
bone marrow disease that affects the blood cells (myelodysplastic syndrome), cancer of the
mouth or lip
Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not
listed in this leaflet. You can also report side effects directly via the national reporting system listed in
Appendix V. By reporting side effects you can help provide more information on the safety of this
medicine.
Strategies to prevent and treat hand-foot syndrome include:

- soaking hands and/or feet in basins of cold water when possible (e.g., while watching television,
reading, or listening to the radio);
36
- keeping hands and feet uncovered (no gloves, socks, etc.);
- staying in cool places;
- taking cool baths during hot weather;
- avoiding vigorous exercise that might cause trauma to the feet (e.g., jogging);
- avoiding exposure of skin to very hot water (e.g., jacuzzis, saunas);
- avoiding tight fitting footwear or high-heeled shoes.
Pyridoxine (Vitamin B6):

- vitamin B6 is available without prescription;
- take 50-150 mg daily beginning at the first signs of redness or tingling.
5. How to store Caelyx pegylated liposomal
Keep this medicine 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 2°C to 8°C.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
should not be longer than 24 hours at 2°C to 8°C. Partially used vials must be discarded.
Do not use this medicine after the expiry date which is stated on the label and carton.
Do not use this medicine if you notice that it shows evidence of precipitation or any other particulate
matter.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures 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 other ingredients are α-(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ω-
methoxypoly(oxyethylen)-40 sodium salt (MPEG-DSPE), fully hydrogenated soy
phosphatidylcholine (HSPC), cholesterol, ammonium sulphate, sucrose, histidine, water for
injections, hydrochloric acid (for pH-adjustment) and sodium hydroxide (for pH-adjustment).
See section 2.
Caelyx pegylated liposomal concentrate for solution for infusion: vials which provide 10 ml (20 mg)
or 25 ml (50 mg).
What Caelyx pegylated liposomal looks like and contents of the pack
Caelyx pegylated liposomal is sterile, translucent and red. Caelyx pegylated liposomal is available in
glass vials as a single pack or packs of ten vials.
Not all pack sizes may be marketed.
Marketing Authorisation Holder

Baxter Holding B.V.
Kobaltweg 49,
3542 CE Utrecht,
Netherlands
37
Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
For any information about this medicine, please contact the local representative of the Marketing
Authorisation 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
38
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
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/.
39
The following information is intended for medical or healthcare professionals only (see section 3):
Caution must be exercised in handling Caelyx pegylated liposomal dispersion. The use of gloves is
required. If Caelyx pegylated liposomal comes into contact with skin or mucosa, wash immediately
and thoroughly with soap and water. Caelyx pegylated liposomal must be handled and disposed of in a
manner consistent with that of other anticancer medicinal products.
Determine the dose of Caelyx pegylated liposomal to be administered (based upon the recommended
dose and the patient's body surface area). Take the appropriate volume of Caelyx pegylated liposomal
up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or
bacteriostatic agent is present in Caelyx pegylated liposomal. The appropriate dose of Caelyx
pegylated liposomal must be diluted in 5% (50 mg/ml) glucose solution for infusion prior to
administration. For doses < 90 mg, dilute Caelyx pegylated liposomal in 250 ml, and for doses
≥ 90 mg, dilute Caelyx pegylated liposomal in 500 ml.
To minimise the risk of infusion reactions, the initial dose is administered at a rate no greater than
1 mg/minute. If no infusion reaction is observed, subsequent Caelyx pegylated liposomal infusions
may be administered over a 60-minute period.
In the breast cancer trial program, modification of the infusion was permitted for those patients
experiencing 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 for 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, immediately discontinue the
infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart
at a slower rate.
The use of any diluent other than 5% (50 mg/ml) glucose solution for infusion, or the presence of any
bacteriostatic agent such as benzyl alcohol may cause precipitation of Caelyx pegylated liposomal.
It is recommended that the Caelyx pegylated liposomal infusion line be connected through the side
port of an intravenous infusion of 5% (50 mg/ml) glucose. Infusion may be given through a peripheral
vein. Do not use with in-line filters.
40

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml of Caelyx pegylated liposomal contains 2 mg doxorubicin hydrochloride in a pegylated

Caelyx pegylated liposomal is doxorubicin hydrochloride encapsulated in liposomes with

Excipients with known effect

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

The dispersion is sterile, translucent and red.

4.1 Therapeutic indications

Caelyx pegylated liposomal is indicated:

4.2 Posology and method of administration

For all patients

Guidelines for Caelyx pegylated liposomal dose modification

Table 1. Palmar–Plantar erythrodysesthesia

Table 3. Haematological toxicity (ANC or platelets) – Management of patients with breast or

Table 4. Dosage adjustments for Caelyx pegylated liposomal + bortezomib combination

AIDS-related KS patients with splenectomy

Do not administer Caelyx pegylated liposomal as a bolus injection or undiluted dispersion. It is

Breast cancer/Ovarian cancer/Multiple myeloma

Persistent severe myelosuppression, may result in superinfection or haemorrhage.

In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen,

Secondary haematological malignancies

Secondary oral neoplasms

Palmar plantar erythrodysaesthesia syndrome (PPE)

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

4.7 Effects on ability to drive and use machines

Summary of the safety profile

Tabulated list of adverse reactions

Table 5: Adverse reactions in patients treated with Caelyx pegylated liposomal

Description of selected adverse reactions

Radiation recall phenomenon

5.1 Pharmacodynamic properties

Clinical efficacy and safety

5.2 Pharmacokinetic properties

Caelyx pegylated liposomal is a long-circulating pegylated liposomal formulation of doxorubicin

Breast cancer patients

Ovarian cancer patients

Table 6. Pharmacokinetic parameters in Caelyx pegylated liposomal-treated AIDS-KS

5.3 Preclinical safety data

Mutagenicity and carcinogenicity

6.1 List of excipients

6.3 Shelf life

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

6.5 Nature and contents of container

Caelyx pegylated liposomal is supplied as a single pack or packs of ten vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Baxter Holding B.V.

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 June 1996

10. DATE OF REVISION OF THE TEXT

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE