ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Caelyx 2 mg/ml concentrate for solution for infusion
2.
One ml of Caelyx contains 2 mg doxorubicin hydrochloride in a pegylated liposomal formulation.
Caelyx, a liposome formulation, 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.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion
The suspension is sterile, translucent and red.
4.
Caelyx 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 CD
4
counts
(< 200 CD
4
lymphocytes/mm
3
) and extensive mucocutaneous or visceral disease.
Caelyx 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).
Caelyx should only be administered under the supervision of a qualified oncologist specialised in the
administration of cytotoxic agents.
Caelyx exhibits unique pharmacokinetic properties and must not be used interchangeably with other
formulations of doxorubicin hydrochloride.
Breast cancer/Ovarian cancer:
Caelyx is administered intravenously at a dose of 50 mg/m
2
once every 4 weeks for as long as the
disease does not progress and the patient continues to tolerate treatment.
Multiple Myeloma
:
Caelyx 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
2
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.
For doses < 90 mg: dilute Caelyx in 250 ml 5 % (50 mg/ml) glucose solution
for infusion.
For doses ≥ 90 mg: dilute Caelyx in 500 ml 5 % (50 mg/ml) glucose solution for infusion.
To minimize 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 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:
Caelyx is administered intravenously at 20 mg/m
2
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.
The dose of Caelyx is diluted in 250 ml 5 % (50 mg/ml) glucose solution for infusion and
administered by intravenous infusion
over 30 minutes.
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.
Do not administer Caelyx as a bolus injection or undiluted solution. It is recommended that the Caelyx
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 must not be given by the
intramuscular or subcutaneous route (see section 6.6).
To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or
haematological toxicity, the dose may be reduced or delayed.
Guidelines for Caelyx 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 addressed in 4.8.
3
Guidelines For Caelyx Dose Modification
Table 1. PALMAR – PLANTAR ERYTHRODYSESTHESIA
Week After Prior Caelyx Dose
Toxicity Grade At
Current Assessment
Week 4
Week 5
Week 6
Grade 1
(mild erythema,
swelling, or
desquamation not
interfering with daily
activities)
Redose unless
patient has
experienced a
previous Grade 3 or
4 skin toxicity, in
which case wait an
additional week
Redose unless
patient has
experienced a
previous Grade 3 or
4 skin toxicity, in
which case wait an
additional week
Decrease dose by
25 %; return to
4 week interval
Grade 2
(erythema,
desquamation, or
swelling interfering
with, but not
precluding normal
physical activities;
small blisters or
ulcerations less than
2 cm in diameter)
Wait an additional
week
Wait an additional
week
Decrease dose by
25 %; return to
4 week interval
Grade 3
(blistering, ulceration,
or swelling interfering
with walking or
normal daily
activities; cannot wear
regular clothing)
Wait an additional
week
Wait an additional
week
Withdraw patient
Grade 4
(diffuse or local
process causing
infectious
complications, or a
bedridden state or
hospitalization)
Wait an additional
week
Wait an additional
week
Withdraw patient
4
Table 2. STOMATITIS
Week after Prior Caelyx Dose
Toxicity Grade At
Current Assessment
4
5
6
Grade 1
(painless ulcers,
erythema, or mild
soreness)
Redose unless
patient has
experienced a
previous Grade 3 or
4 stomatitis in which
case wait an
additional week
Redose unless
patient has
experienced a
previous Grade 3 or
4 stomatitis in which
case wait an
additional week
Decrease dose by
25 %; return to
4 week interval
or
withdraw patient per
physician’s
assessment
Grade 2
(painful erythema,
oedema, or ulcers, but
can eat)
Wait an additional
week
Wait an additional
week
Decrease dose by
25 %; return to
4 week interval
or
withdraw patient per
physician’s
assessment
Grade 3
(painful erythema,
edema, or ulcers, but
cannot eat)
Wait an additional
week
Wait an additional
week
Withdraw patient
Grade 4
(requires parenteral or
enteral support)
Wait an additional
week
Wait an additional
week
Withdraw patient
5
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.
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 in combination with bortezomib who experience
PPE or stomatitis, the Caelyx 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 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 + BORTEZOMIB COMBINATION
THERAPY - PATIENTS WITH MULTIPLE MYELOMA
Patient Status
Caelyx
Bortezomib
Fever ≥ 38
○
C and
ANC < 1,000/mm
3
Do not dose this cycle if
before Day 4; if after Day 4,
reduce next dose by 25 %.
Reduce next dose by 25 %.
On any day of medicine
administration after Day 1 of
each cycle:
Platelet count < 25,000/mm
3
Hemoglobin < 8 g/dl
ANC < 500/mm
3
Do not dose this cycle if
before Day 4; if after Day 4
reduce next dose by 25 % in
the following cycles if
bortezomib is reduced for
hematologic toxicity.*
Do not dose; if 2 or more
doses are not given in a cycle,
reduce dose by 25 % in
following cycles.
Grade 3 or 4 non-hematologic
medicine related toxicity
Do not dose until recovered to
Grade < 2 and reduce dose by
25 % for all subsequent doses.
Do not dose until recovered
to Grade < 2 and reduce dose
by 25 % for all subsequent
doses.
Neuropathic pain or peripheral
neuropathy
No dosage adjustments.
See the SPC for bortezomib.
*
for more information on bortezomib dosing and dosage adjustment, see the SPC for bortezomib
Patients with impaired hepatic function
:
Caelyx 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 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 can be administered to patients with
liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of
6
the normal range. Prior to Caelyx administration, evaluate hepatic function using conventional clinical
laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.
Patients with impaired renal function
:
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 clearance is not influenced by
renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than
30 ml/min.
AIDS-KS patients with splenectomy
:
As there is no experience with Caelyx in patients who have had
splenectomy, treatment with Caelyx is not recommended.
Paediatric patients
:
The experience in children is limited. Caelyx is not recommended in patients
below 18 years of age.
Elderly patients
:
Population based analysis demonstrates that age across the range tested
(21 – 75 years) does not significantly alter the pharmacokinetics of Caelyx.
•
Hypersensitivity to the active substance or to any of the excipients.
Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or
systemic alfa-interferon.
Cardiac toxicity
: It is recommended that all patients receiving Caelyx 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 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
therapy and repeated periodically during treatment. The evaluation of left ventricular function is
considered to be mandatory before each additional administration of Caelyx that exceeds a lifetime
cumulative anthracycline dose of 450 mg/m
2
.
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 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 only when the benefit
outweighs the risk to the patient.
Exercise caution in patients with impaired cardiac function who receive Caelyx.
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.
7
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/m
2
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/m
2
)
is similar to the 20 mg/m
2
profile in patients with AIDS-KS (see section 4.8).
Myelosuppression
: Many patients treated with Caelyx 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/m
2
, 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 vs.
topotecan, the incidence of treatment related sepsis was substantially less in the Caelyx-treated ovarian
cancer patients as compared to the topotecan treatment group. A similar low incidence of
myelosuppression was seen in patients with metastatic breast cancer receiving Caelyx 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 therapy, and at a minimum, prior to each dose of
Caelyx.
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. Patients and
doctors must be aware of this higher incidence and take action as appropriate.
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.
Given the difference in pharmacokinetic profiles and dosing schedules, Caelyx should not be used
interchangeably with other formulations of doxorubicin hydrochloride.
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. Very rarely, convulsions also have been observed in
relation to infusion reactions (see section 4.8). 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).
Diabetic patients
: Please note that each vial of Caelyx contains sucrose and the dose is administered in
5 % (50 mg/ml) glucose solution for infusion.
For common adverse events which required dose modification or discontinuation see section 4.8.
8
No formal medicinal product interaction studies have been performed with Caelyx, 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, 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.
Pregnancy
:
Doxorubicin hydrochloride is suspected to cause serious birth defects when administered
during pregnancy. Therefore, Caelyx should not be used during pregnancy unless clearly necessary.
Women of child-bearing potential must
be advised to avoid pregnancy while they or their male partner
are receiving Caelyx and in the six months following discontinuation of Caelyx therapy (see
section 5.3).
Lactation
: It is not known whether Caelyx 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 treatment. Health experts recommend that HIV infected women do not breast-feed
their infants under any circumstances in order to avoid transmission of HIV.
Caelyx 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. Patients who suffer from these effects must avoid driving and operating machinery.
The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m
2
every
4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was
44.0 % - 46.1 %. These effects were mostly mild, with severe (Grade III) cases reported in 17 % -
19.5 %. The reported incidence of life-threatening (Grade IV) cases was < 1 %. PPE infrequently
resulted in permanent treatment discontinuation (3.7 % - 7.0 %). 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 one - two 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, which may be
initiated for
4 to 7 days after treatment with Caelyx 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. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer
patient populations, whereas the AIDS-KS Program (20 mg/m
2
every 2 weeks), myelosuppression
(mostly leukopaenia) was the most common side effect (see AIDS-KS). PPE was reported in 16 % of
multiple myeloma patients treated with Caelyx plus bortezomib combination therapy. Grade 3 PPE
was reported in 5 % of patients. No grade 4 PPE was reported. The most frequently reported
9
(medicine-related treatment-emergent) adverse events in combination therapy (Caelyx + bortezomib)
were nausea (40 %), diarrhoea (35 %), neutropaenia (33 %), thrombocytopaenia (29 %), vomiting
(28 %), fatigue (27 %), and constipation (22 %).
Breast cancer program:
509 patients with advanced breast cancer who had not received prior
chemotherapy for metastatic disease were treated with Caelyx (n=254) at a dose of 50 mg/m
2
every
4 weeks, or doxorubicin (n=255) at a dose of 60 mg/m
2
every 3 weeks, in a phase III clinical trial (I97-
328). The following common adverse events were reported more often with doxorubicin than with
Caelyx: nausea (53 % vs. 37 %; Grade III/IV 5 % vs. 3 %), vomiting (31 % vs. 19 %; Grade III/IV
4 % vs. less than 1 %), any alopecia (66 % vs. 20 %), pronounced alopecia (54 % vs.7 %), and
neutropaenia (10 % vs. 4 %; Grade III/IV 8 % vs. 2 %).
Mucositis (23 % vs. 13 %; Grade III/IV 4 % vs. 2 %), and stomatitis (22 % vs. 15 %; Grade III/IV 5 %
vs. 2 %) were reported more commonly with Caelyx than with doxorubicin. The average duration of
the most common severe (Grade III/IV) events for both groups was 30 days or less. See Table 5 for
complete listing of undesirable effects reported in Caelyx-treated patients.
The incidence of life threatening (Grade IV) haematologic effects was < 1.0 % and sepsis was reported
in 1 % of patients. Growth factor support or transfusion support was necessary in 5.1 % and 5.5 % of
patients, respectively (see section 4.2).
Clinically significant laboratory abnormalities (Grades III and IV) in this group was low with elevated
total bilirubin, AST and ALT reported in 2.4 %, 1.6 % and < 1 % of patients respectively. No
clinically significant increases in serum creatinine were reported.
10
Table 5. Treatment Related Undesirable Effects Reported in Breast Cancer Clinical Trials
(50 mg/m
2
every 4 weeks) (Caelyx-treated patients)
by Severity, MedDRA System Organ Class and Preferred Term
Very Common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100)
CIOMS III
AE by body system
Breast Cancer
All Severities
n=254
(≥ 5 %)
Breast Cancer
Grades III/IV
n=254
(≥ 5 % )
Breast Cancer
n=404
(1-5 %)
not previously reported
in clinical trials
Infections and
infestations
Common
Pharyngitis
Folliculitis, fungal
infection, cold sores
(non-herpetic), upper
respiratory tract
infection
Uncommon
Pharyngitis
Blood and lymphatic
system disorders
Common
Leukopaenia, anaemia,
neutropaenia,
thrombocytopaenia
Leukopaenia, anaemia
Thrombocythemia
Uncommon
Neutropaenia
Metabolism and
nutrition disorders
Very Common
Anorexia
Common
Anorexia
Nervous system
disorders
Common
Paresthesia
Paresthesia
Peripheral neuropathy
Uncommon
Somnolence
Eye Disorders
Common
Lacrimation, blurred
vision
Cardiac disorders
Common
Ventricular arrhythmia
Respiratory, thoracic
and mediastinal
disorders
Common
Epistaxis
11
Gastrointestinal
disorders
Very Common
Nausea, stomatitis,
vomiting
Common
Abdominal pain,
constipation, diarrhoea,
dyspepsia, mouth
ulceration
Abdominal pain
,
diarrhoea, nausea,
stomatitis
Oral pain
Uncommon
Mouth ulceration,
constipation, Vomiting
Skin and
subcutaneous tissue
disorders
Very Common
PPE*, alopecia, rash
PPE*
Common
Dry skin, skin
discolouration,
pigmentation abnormal,
erythema
Rash
Bullous eruption,
dermatitis,
erythematous rash, nail
disorder, scaly skin
Uncommon
Pigmentation
abnormal, erythema
Musculoskeletal and
connective tissue
disorders
Common
Leg cramps, bone pain,
musculoskeletal pain
Reproductive system
and breast disorders
Common
Breast pain
General disorders
and administration
site conditions
Very Common
Asthenia, fatigue,
mucositis NOS
Common
Weakness, fever, pain
Asthenia, mucositis
NOS
Oedema, leg oedema.
Uncommon
Fatigue, weakness,
pain
*
palmar-plantar erythrodysesthesia (Hand- foot syndrome).
Ovarian cancer program
:
512 patients with ovarian cancer (a subset of 876 solid tumour patients)
were treated with Caelyx at a dose of 50 mg/m
2
in clinical trials. See Table 6 for undesirable effects
reported in Caelyx-treated patients.
Table 6 Treatment Related Undesirable Effects Reported in Ovarian Cancer Clinical Trials
(50 mg/m
2
every 4 weeks) (Caelyx-treated patients)
by Severity, MedDRA System Organ Class and Preferred Term
Very Common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100)
CIOMS III
12
AE by body system
Ovarian Cancer
All Severities
n=512
(≥ 5 % )
Ovarian Cancer
Grades III/IV
n=512
(≥ 5 %)
Ovarian Cancer
n=512
(1-5% )
Infections and
infestations
Common
Pharyngitis
Infection, oral
moniliasis, herpes
zoster, urinary tract
infection
Uncommon
Pharyngitis
Blood and
lymphatic system
disorders
Very Common
Leukopaenia, anaemia,
neutropaenia,
thrombocytopaenia
Neutropaenia
Common
Leukopaenia, anaemia,
thrombocytopaenia
Hypochromic anaemia
Immune system
disorders
Common
Allergic reaction
Metabolism and
nutrition disorders
Very Common
Anorexia
Common
Dehydration, cachexia
Uncommon
Anorexia
Psychiatric
disorders
Common
Anxiety,
depression,
insomnia
Nervous system
disorders
Common
Paresthesia, somnolence
Headache,
dizziness,
neuropathy, hypertonia
Uncommon
Paresthesia, somnolence
Eye disorders
Common
Conjunctivitis
Cardiac disorders
Common
Cardiovascular disorder
Vascular disorders
Common
Vasodilatation
13
Respiratory,
thoracic and
mediastinal
disorders
Common
Dyspnoea, increased
cough
Gastrointestinal
disorders
Very Common
Constipation, diarrhoea,
nausea, stomatitis,
vomiting
Common
Abdominal pain,
dyspepsia, mouth
ulceration
Nausea, stomatitis,
vomiting, abdominal
pain, diarrhoea
Mouth ulceration,
esophagitis, nausea and
vomiting, gastritis,
dysphagia, dry mouth,
flatulence, gingivitis
,
taste perversion
Uncommon
Constipation, dyspepsia,
mouth ulceration
Skin and
subcutaneous tissue
disorders
Very Common
PPE*, alopecia, rash
PPE*
Common
Dry skin, skin
discolouration
Alopecia, rash
Vesiculobullous rash,
pruritus, exfoliative
dermatitis, skin
disorder,
maculopapular rash,
sweating, acne, skin
ulcer
Musculoskeletal
and connective
tissue disorders
Common
Back pain, myalgia
Renal and urinary
disorders
Common
Dysuria
Reproductive
system and breast
disorders
Common
Vaginitis
General disorders
and administration
site conditions
Very Common
Asthenia, mucous
membrane disorder
Common
Fever, pain
Asthenia, mucous
membrane disorder, pain
Chills, chest pain,
malaise, peripheral
oedema
Uncommon
Fever
14
Investigations
Common
Weight loss
*
palmar-plantar erythrodysesthesia (Hand- foot syndrome).
Myelosuppression was mostly mild or moderate and manageable. Sepsis related to leukopaenia was
observed infrequently (< 1 %). Growth factor support was required infrequently (< 5 %) and
transfusion support was required in approximately 15 % of patients (see section 4.2).
In a subset of 410 patients with ovarian cancer, clinically significant laboratory abnormalities
occurring in clinical trials with Caelyx included increases in total bilirubin (usually in patients with
liver metastases) (5 %) and serum creatinine levels (5 %). Increases in AST were less frequently
(< 1 %) reported.
Solid tumour patients: in a larger cohort of 929 patients with solid tumours (including breast cancer
and ovarian cancer) predominantly treated at a dose of 50 mg/m
2
every 4 weeks, the safety profile and
incidence of adverse effects are comparable to those of the patients treated in the pivotal breast cancer
and ovarian cancer trials.
Multiple Myeloma program:
Of
646 patients with multiple myeloma who have received at least 1 prior
therapy, 318 patients were treated with combination therapy of Caelyx 30 mg/m
2
as a one hour
intravenous infusion administered on day 4 following bortezomib which is administered at 1.3 mg/m²
on days 1, 4, 8, and 11, every three weeks or with bortezomib monotherapy in a phase III clinical trial.
See Table 7 for adverse effects reported in ≥ 5 % patients treated with combination therapy of Caelyx
plus bortezomib.
Neutropaenia, thrombocytopaenia, and anaemia were the most frequently reported hematologic events
reported with both combination therapy of Caelyx plus bortezomib and bortezomib monotherapy. The
incidence of grade 3 and 4 neutropaenia was higher in the combination therapy group than in the
monotherapy group (28 % vs. 14 %). The incidence of grade 3 and 4 thrombocytopaenia was higher in
the combination therapy group than in the monotherapy group (22 % vs. 14 %). The incidence of
anaemia was similar in both treatment groups (7 % vs. 5 %).
Stomatitis was reported more frequently in the combination therapy group (16 %) than in the
monotherapy group (3 %), and most cases were grade 2 or less in severity. Grade 3 stomatitis was
reported in 2 % of patients in the combination therapy group. No grade 4 stomatitis was reported.
Nausea and vomiting were reported more frequently in the combination therapy group (40 % and
28 %) than in the monotherapy group (32 % and 15 %) and were mostly grade 1 and 2 in severity.
Treatment discontinuation of one or both agents due to adverse events was seen in 38 % of patients.
Common adverse events which led to treatment discontinuation of bortezomib and Caelyx included
PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopaenia, decreased
ejection fraction, and fatigue.
Table 7. Treatment Related Undesirable Effects Reported in Multiple Myeloma
Clinical Trial (Caelyx 30 mg/m
2
in combination with bortezomib every 3 weeks)
by Severity, MedDRA System Organ Class and Preferred Term
Very Common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100)
CIOMS III
AE by body system
All Severities
n=318
(≥ 5 %)
Grades III/IV**
n=318
(≥ 5 % )
All Severities
n=318
(1-5 %)
15
Infections and
infestations
Common
Herpes simplex, herpes
zoster
Herpes zoster
Pneumonia,
nasopharyngitis, upper
respiratory tract infection,
oral candidiasis
Blood and lymphatic
system disorders
Very Common
Anaemia, neutropaenia,
thrombocytopaenia
Neutropaenia,
thrombocytopaenia
Common
Leukopaenia
Anaemia,
leukopaenia
Febrile neutropaenia,
lymphopaenia
Metabolism and
Nutrition disorders
Very Common
Anorexia
Common
Decreased appetite
Anorexia
Dehydration,
hypokalaemia,
hyperkalaemia,
hypomagnesaemia,
hyponatraemia,
hypocalcaemia
Uncommon
Decreased appetite
Psychiatric disorders
Common
Insomnia
Anxiety
Nervous system
disorders
Very Common
Peripheral sensory
neuropathy, neuralgia,
headache
Common
Neuropathy peripheral,
neuropathy,
paraesthesia,
polyneuropathy,
dizziness, dysgeusia
Neuralgia,
peripheral
neuropathy,
neuropathy
Lethargy, hypoaesthesia,
syncope, dysaesthesia
Uncommon
Headache,
peripheral sensory
neuropathy,
paraesthesia,
dizziness
Eye disorders
Common
Conjunctivitis
Vascular disorders
Common
Hypotension, orthostatic
hypotension, flushing,
hypertension, phlebitis
16
Respiratory,
thoracic, and
mediastinal disorders
Common
Dyspnoea
Cough, epistaxis
exertional dyspnoea
Uncommon
Dyspnoea
Gastrointestinal
disorders
Very Common
Nausea, diarrhoea,
vomiting, constipation,
stomatitis
Common
Abdominal pain,
dyspepsia
Nausea, diarrhoea,
vomiting, stomatitis
Upper abdominal pain,
mouth ulceration, dry
mouth, dysphagia,
aphthous stomatitis
Uncommon
Constipation,
abdominal pain,
dyspepsia
Skin and
subcutaneous tissue
disorders
Very Common
PPE*, rash
Common
Dry skin
PPE*
Pruritus, papular rash,
allergic dermatitis,
erythema, skin
hyperpigmentation,
petechiae, alopecia,
medicine eruption
Uncommon
Rash
Musculoskeletal and
connective tissue
disorders
Common
Pain in extremity
Arthralgia, myalgia,
muscle spasms, muscular
weakness, musculoskeletal
pain, musculoskeletal
chest pain
Reproductive system
and breast disorders
Common
Scrotal erythema
General disorders
and administration
site conditions
Very Common
Asthenia, fatigue,
pyrexia
Common
Asthenia,
fatigue
Peripheral oedema, chills,
influenza-like illness,
malaise, hyperthermia
Uncommon
Pyrexia
17
Investigations
Common
Weight decreased
Aspartate
aminotransferase
increased, ejection fraction
decreased, blood
creatinine increased,
alanine aminotransferase
increased
*
Palmar-plantar erythrodysesthesia (Hand-foot syndrome).
**
Grade 3/4 adverse events are based on the adverse event terms of all severities with an overall incidence ≥ 5 % (see
adverse events listed in first column).
AIDS-KS program
: Clinical studies on AIDS-KS patients treated at 20 mg/m
2
with Caelyx show that
myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring
very commonly (in approximately one-half of the patients).
Leukopaenia is the most frequent undesirable effect experienced with Caelyx in this population;
neutropaenia, anaemia and thrombocytopaenia have been observed. These effects may occur early on
in treatment. Haematological toxicity may require dose reduction or suspension or delay of therapy.
Temporarily suspend Caelyx treatment in patients when the ANC count is < 1,000/mm
3
and/or the
platelet count is < 50,000/mm
3
. G-CSF (or GM-CSF) may be given as concomitant therapy to support
the blood count when the ANC count is < 1,000/mm
3
in subsequent cycles. The haematological
toxicity for ovarian cancer patients is less severe than in the AIDS-KS setting (see section for ovarian
cancer patients above).
Respiratory undesirable effects commonly occurred in clinical studies of Caelyx and may be related to
opportunistic infections in the AIDS population. Opportunistic infections (OI’s) are observed in KS
patients after administration with Caelyx, 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 carinii
pneumonia, and mycobacterium avium
complex.
(Very common (> 1/10); Common (> 1/100, < 1/10); Uncommon (> 1/1,000, < 1/100)) were as
follows:
Infections and infestations:
Common: oral moniliasis
Blood and lymphatic system disorders:
Very common: neutropaenia, anaemia, leukopaenia
Common: thrombocytopaenia
Metabolism and nutrition disorders:
Common
:
anorexia
Psychiatric disorders:
Uncommon
:
confusion
Nervous system disorders:
Common
:
dizziness
Uncommon: paresthesia
Eye disorders:
Common
:
retinitis
Vascular disorders:
18
Common: vasodilatation
Respiratory, thoracic and mediastinal disorders:
Common
:
dyspnoea
Gastrointestinal disorders:
Very common
:
nausea
Common
:
diarrhoea, stomatitis, vomiting, mouth ulceration, abdominal pain, glossitis, constipation,
nausea and vomiting
Skin and subcutaneous tissue disorders:
Common
:
alopecia, rash
Uncommon: palmar-plantar erythrodysesthesia (PPE)
General disorders and administration site conditions:
Common: asthenia, fever, infusion-associated acute reactions
Investigations:
Common
:
weight loss.
Other less frequently (< 5 %) observed undesirable effects included hypersensitivity reactions
including anaphylactic reactions.
Following marketing, bullous eruption has been reported rarely in
this population.
Clinically significant laboratory abnormalities frequently (≥ 5 %) occurred including increases in
alkaline phosphatase; AST and bilirubin which were believed to be related to the underlying disease
and not Caelyx. Reduction in haemoglobin and platelets were less frequently (< 5 %) reported. Sepsis
related to leukopaenia was rarely (< 1 %) observed. Some of these abnormalities may have been
related to the underlying HIV infection and not Caelyx.
All patients
:
100 out of 929 patients (10.8 %) with solid tumours were described as having an
infusion-associated reaction during treatment with Caelyx as defined by the following Costart terms:
allergic reaction, anaphylactoid reaction, asthma, face oedema, hypotension, vasodilatation, urticaria,
back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnoea,
pharyngitis, rash, pruritus, sweating, injection site reaction and medicinal product interaction.
Permanent treatment discontinuation was infrequently reported at 2 %. A similar incidence of infusion
reactions (12.4 %) and treatment discontinuation (1.5 %) was observed in the breast cancer program
.
In patients with multiple myeloma receiving Caelyx plus bortezomib, infusion-associated reactions
have been reported at a rate of 3 %. In patients with AIDS-KS, infusion-associated reactions, were
characterised by flushing, shortness of breath, facial oedema, headache, chills, back pain, tightness in
the chest and throat and/or hypotension and can be expected at the rate of 5 % to 10 %. Very rarely,
convulsions have been observed in relation to infusion reactions. In all patients, infusion associated
reactions occurred primarily during the first infusion. Temporarily stopping the infusion usually
resolves these symptoms without further therapy. In nearly all patients, Caelyx treatment can be
resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the
first treatment cycle with Caelyx (see section 4.2).
Myelosuppression associated with anaemia, thrombocytopaenia, leukopaenia, and rarely febrile
neutropaenia, has been reported in Caelyx -treated patients.
Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin
hydrochloride and was frequently reported in patients receiving Caelyx. It did not interfere with
patients completing therapy and no dosage adjustments are generally required, unless stomatitis is
affecting a patient’s ability to eat. In this case, the dose interval may be extended by 1 - 2 weeks or the
dose reduced (see section 4.2).
19
An increased incidence of congestive heart failure is associated with doxorubicin therapy at
cumulative lifetime doses > 450 mg/m
2
or at lower doses for patients
with cardiac risk factors.
Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of Caelyx
greater than 460 mg/m
2
indicate no evidence of anthracycline-induced cardiomyopathy. The
recommended dose of Caelyx for AIDS-KS patients is 20 mg/m
2
every two-to-three weeks. The
cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients
(> 400 mg/m
2
) would require more than 20 courses of Caelyx therapy over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative
anthracycline doses of 509 mg/m
2
–
1,680 mg/m
2
.
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 %) randomized subjects (10 treated with
Caelyx at a dose of 50 mg/m
2
/every 4 weeks versus 48 treated with doxorubicin at a dose of
60 mg/m
2
/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 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/m
2
/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m
2
,
the
incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with
Caelyx 50 mg/m
2
/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/m
2
, 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/m
2
), discontinued study treatment because of clinical symptoms of congestive heart
failure.
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.
Although local necrosis following extravasation has been reported very rarely, Caelyx 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 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 must not be given by the intramuscular or subcutaneous route.
Recall of skin reaction due to prior radiotherapy has rarely occurred with Caelyx administration.
Following the marketing of Caelyx, serious skin conditions including erythema multiforme, Stevens
Johnson syndrome and toxic epidermal necrolysis have been reported very rarely.
In patients treated with Caelyx, cases of venous thromboembolism, including thrombophlebitis,
venous thrombosis and pulmonary embolism have been seen uncommonly. However, because patients
with cancer are at increased risk for thromboembolic disease, a causal relationship cannot be
determined.
20
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code:
L01DB.
The active ingredient of Caelyx 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.
A phase III randomized study of Caelyx versus doxorubicin in patients with metastatic breast cancer
was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority
between Caelyx 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 than with doxorubicin (HR=3.16,
p < 0.001). At cumulative doses greater than 450 mg/m
2
there were no cardiac events with Caelyx.
A phase III comparative study of Caelyx 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-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, 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
(95 % CI; 1.066, 1.923), p=0.017. The survival rates at 1, 2 and 3 years were 74.1 %, 51.2 % and
28.4 % respectively on Caelyx, compared to 66.2 %, 31.0 % and 17.5 % on topotecan.
The treatments were similar in the sub-group of patients with platinum refractory disease: HR of 1.069
(95 % CI; 0.823, 1.387), p=0.618. The survival rates at 1, 2 and 3 years were 41.5 %, 21.1 % and
13.8 % respectively on Caelyx, compared to 43.2 %, 17.2 % and 9.5 % on topotecan.
A phase III randomized, parallel-group, open-label, multicentre study comparing the safety and
efficacy of Caelyx 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 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 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 plus
21
bortezomib combination therapy patients. These results, though not mature, constituted the protocol
defined final analysis.
5.2 Pharmacokinetic properties
Caelyx 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 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 in humans differ significantly from those reported in the
literature for standard doxorubicin hydrochloride preparations. At lower doses (10 mg/m
2
– 20 mg/m
2
)
Caelyx displayed linear pharmacokinetics. Over the dose range of 10 mg/m
2
– 60 mg/m
2
Caelyx
displayed non-linear pharmacokinetics. Standard doxorubicin hydrochloride displays extensive tissue
distribution (volume of distribution: 700 to 1,100 l/m
2
) and a rapid elimination clearance (24 to
73 l/h/m
2
). In contrast, the pharmacokinetic profile of Caelyx indicates that Caelyx 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 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 should not be used interchangeably with other formulations of doxorubicin hydrochloride.
Population pharmacokinetics
The pharmacokinetics of Caelyx was evaluated in 120 patients from 10 different clinical trials using
the population pharmacokinetic approach. The pharmacokinetics of Caelyx over the dose range of
10 mg/m
2
to 60 mg/m
2
was best described by a two compartment non-linear model with zero order
input and Michaelis-Menten elimination. The mean intrinsic clearance of Caelyx was 0.030 l/h/m
2
(range 0.008 to 0.152 l/h/m
2
) and the mean central volume of distribution was 1.93 l/m
2
(range 0.96 –
3.85 l/m
2
) 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 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/m
2
(range 0.008 - 0.027 l/h/m
2
), the mean central volume of
distribution was 1.46 l/m
2
(range 1.10 - 1.64 l/m
2
). The mean apparent half-life was 71.5 hours (range
45.2 - 98.5 hours).
Ovarian cancer patients
The pharmacokinetics of Caelyx 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/m
2
(range 0.009 – 0.041 l/h/m
2
), the mean central volume of
distribution was 1.95 l/m
2
(range 1.67 – 2.40 l/m
2
). The mean apparent half-life was 75.0 hours (range
36.1 – 125 hours).
22
AIDS-KS patients
The plasma pharmacokinetics of Caelyx were evaluated in 23 patients with KS who received single
doses of 20 mg/m
2
administered by a 30-minute infusion. The pharmacokinetic parameters of Caelyx
(primarily representing pegylated liposomal doxorubicin hydrochloride and low levels of
unencapsulated doxorubicin hydrochloride) observed after the 20 mg/m
2
doses are presented in
Table 8.
Table 8. Pharmacokinetic Parameters in Caelyx-Treated AIDS-KS Patients
Mean
+
Standard Error
Parameter
20 mg/m
2
(n=23)
Maximum Plasma Concentration* (µg/ml)
8.34 ± 0.49
Plasma Clearance (l/h/m
2
)
Volume of Distribution (l/m
2
)
AUC (µg/ml⋅h)
λ
1
half-life (hours)
λ
2
half-life (hours)
0.041 ± 0.004
2.72 ± 0.120
590.00 ± 58.7
5.2 ± 1.4
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 appears very similar to that
reported in humans who receive long-term infusions of standard doxorubicin hydrochloride. With
Caelyx, 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 is reduced compared
with conventional doxorubicin hydrochloride preparations.
Dermal toxicity
:
In studies performed after the repeated administration of Caelyx to rats and dogs,
serious dermal inflammations and ulcer formations were observed at clinically relevant dosages. In the
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 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, 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, doxorubicin
hydrochloride, the pharmacologically active ingredient of Caelyx, is mutagenic and carcinogenic.
Pegylated placebo liposomes are neither mutagenic nor genotoxic.
Reproductive toxicity
:
Caelyx 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
23
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 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 in patients has not suggested a significant nephrotoxicity liability of Caelyx, these findings
in monkeys may not have relevance to patient risk assessment.
6.
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
sodium hydroxide
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 is supplied as a single pack or packs of ten vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
24
Do not use material that shows evidence of precipitation or any other particulate matter.
Caution must be exercised in handling Caelyx solution. The use of gloves is required. If Caelyx comes
into contact with skin or mucosa, wash immediately and thoroughly with soap and water. Caelyx 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 to be administered (based upon the recommended dose and the patient’s
body surface area). Take the appropriate volume of Caelyx up into a sterile syringe. Aseptic technique
must be strictly observed since no preservative or bacteriostatic agent is present in Caelyx. The
appropriate dose of Caelyx must be diluted in 5 % (50 mg/ml) glucose solution for infusion prior to
administration.
For doses < 90 mg, dilute Caelyx in 250 ml, and for doses ≥ 90 mg, dilute Caelyx 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.
It is recommended that the Caelyx 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.
7.
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
8.
EU/1/96/011/001
EU/1/96/011/002
EU/1/96/011/003
EU/1/96/011/004
9.
Date of first authorization: 21 June 1996
Date of last renewal: 19 May 2006
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
25
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
26
A. MANUFACTURING AUTHORISATION HOLDER 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 OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of Pharmacovigilance, as described in version dated June 2007
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning
before and whilst the product is on the Market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version dated 01 June 2007 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent
updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
27
ANNEX III
LABELLING AND PACKAGE LEAFLET
28
A. LABELLING
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CAELYX CARTON 20 mg/10 ml – 1 vial
CAELYX CARTON 20 mg/10 ml – 10 vials
1.
Caelyx 2 mg/ml concentrate for solution for infusion
Pegylated liposomal doxorubicin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml of Caelyx contains 2 mg pegylated liposomal 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.
1 vial
10 vials
20 mg/10 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use, following dilution in 5 % (50 mg/ml) glucose solution for infusion.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
DO NOT USE INTERCHANGEABLY WITH OTHER FORMULATIONS OF DOXORUBICIN
HYDROCHLORIDE.
8.
EXPIRY DATE
EXP
30
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
Partially used vials should be discarded.
Caelyx should be handled and disposed of in a manner consistent with that of other cytotoxic
medicinal products.
Marketing Authorisation Holder:
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/96/011/001 (1 vial)
EU/1/96/011/002 (10 vials)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Caelyx 20 mg/10 ml
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CAELYX CARTON 50 mg/25 ml – 1 vial
CAELYX CARTON 50 mg/25 ml – 10 vials
1.
Caelyx 2 mg/ml concentrate for solution for infusion
Pegylated liposomal doxorubicin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml of Caelyx contains 2 mg pegylated liposomal 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.
1 vial
10 vials
50 mg/25 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use, following dilution in 5 % (50 mg/ml) glucose solution for infusion.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
DO NOT USE INTERCHANGEABLY WITH OTHER FORMULATIONS OF DOXORUBICIN
HYDROCHLORIDE.
8.
EXPIRY DATE
EXP
32
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
Partially used vials should be discarded.
Caelyx should be handled and disposed of in a manner consistent with that of other cytotoxic
medicinal products.
Marketing Authorisation Holder:
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/96/011/003 (1 vial)
EU/1/96/011/004 (10 vials)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Caelyx 50 mg/25 ml
33
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
CAELYX LABEL 20 mg/10 ml
1.
Caelyx 2 mg/ml concentrate for solution for infusion
Pegylated liposomal doxorubicin hydrochloride
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
20 mg/10 ml
6.
OTHER
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
CAELYX LABEL 50 mg/25 ml
1.
Caelyx 2 mg/ml concentrate for solution for infusion
Pegylated liposomal doxorubicin hydrochloride
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
50 mg/25 ml
6.
OTHER
35
B. PACKAGE LEAFLET
36
PACKAGE LEAFLET: INFORMATION FOR THE USER
Caelyx 2 mg/ml concentrate for solution for infusion
Pegylated liposomal doxorubicin hydrochloride
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Caelyx is and what it is used for
2.
Before you use Caelyx
4.
Possible side effects
5
How to store Caelyx
6.
Further information
1.
WHAT CAELYX IS AND WHAT IT IS USED FOR
Caelyx is an antitumour agent.
Caelyx is used to treat cancer of the breast in patients at risk for heart problems. Caelyx 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 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 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 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 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.
BEFORE YOU USE CAELYX
Do not use Caelyx
-
if you are allergic (hypersensitive) to doxorubicin
hydrochloride or any of the other ingredients
of Caelyx.
Take special care with Caelyx
-
if you are receiving any treatment for heart disease or liver disease;
-
if you are diabetic, because Caelyx 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.
Taking other medicines
Please tell your doctor or pharmacist
37
-
Keep this leaflet. You may need to read it again.
3.
How to use Caelyx
-
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 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 and in the six months following discontinuation of Caelyx treatment.
Because doxorubicin hydrochloride may be harmful to nursing infants, women must discontinue
breast-feeding before starting treatment with Caelyx. 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.
3.
HOW TO USE CAELYX
Caelyx is a unique formulation. It must not be used interchangeably with other formulations of
doxorubicin hydrochloride
.
Caelyx 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 are being treated for breast cancer or ovarian cancer, Caelyx 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 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 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 is repeated every
2 to 3 weeks for 2 - 3 months, then as often as necessary to maintain an improvement in your
condition.
If you use more Caelyx 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, Caelyx can cause side effects, although not everybody gets them.
38
During the infusion of Caelyx, the following reactions may occur: flushing of the face, shortness of
breath, headache, chills, back pain, tightness in the chest and/or throat, sore throat, low or increase in
blood pressure, rapid heart beat, puffing of the face, fever, dizziness, nausea, indigestion, itching, rash
and sweating. In very rare cases, seizures (convulsions) have occurredStinging or swelling of the skin
at the site of injection may also occur. If the drip stings or hurts while you are receiving a dose of
Caelyx, tell your doctor immediately.
Contact your doctor immediately if:
-
you get painful reddening of the skin and/or blisters on the body or in the mouth,
-
you get heart problems,
-
you get mouth sores,
-
you develop a fever or any other sign of an infection,
-
you get sudden shortness of breath or sharp chest pain that may worsen with deep breathing or
coughing,
-
you get swelling, warmth, or tenderness in the soft tissues of your leg, sometimes with pain
which gets worse when you stand or walk.
Between infusions, the following may occur:
-
redness, swelling and sores on the palms of your hands and feet. These effects have been seen
frequently, 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);
-
pain or sores in mouth or throat, nausea, vomiting, stomach pains, diarrhoea, constipation, oral
thrush (a fungal infection in the mouth), sores in nose, bleeding from your nose, cold sores, loss
of appetite, weight loss and tongue inflammation;
-
decrease in the number of white blood cells, which can increase the chances of infections.
Anaemia (reduction in red blood cells) may cause tiredness, and decreased platelets in the blood
may increase the risk of bleeding. In rare cases, having low white blood cells may lead to severe
infection. Laboratory values related to the function of the liver may either increase or decrease
while on Caelyx. It is because of the potential changes in your blood cells that you will have
regular blood tests
.
From a clinical study in patients with AIDS-KS comparing Caelyx against
another treatment (bleomycin/vincristine), there may be a higher chance of some infections with
Caelyx. However, in contrast to the experience with patients with AIDS-KS, when Caelyx was
compared to a standard treatment for advanced ovarian cancer (topotecan), the risk of infections
was substantially lower in the Caelyx-treated patients. The risk of low blood counts and
infections was similarly low in breast cancer studies. Some of these effects may be related to
your disease and not to Caelyx;
-
general feeling of tiredness, sleepiness, confusion, dizziness, weakness, bone pain, breast pain,
muscle pain, leg cramps or swelling, general swelling, inflammation of the retina (the light-
detecting membrane of the eye), increased tear production, blurred vision, feeling of pins and
needles or pain in hands and feet;
-
hair loss, inflammation of hair follicles, scaly skin, inflammation or rash, abnormal skin
pigmentation (colouring), and nail disorder ;
- heart problems, e.g., irregular heart beat, enlarged blood vessels;
-
fever, increased temperature or any other sign of infection which may be related to your disease;
-
respiratory problems, i.e., difficulty in breathing or coughing which may be linked to infections
you have caught as a result of your disease;
- if you have previously had skin reactions, i.e., pain, redness and dryness of skin, during
treatment with radiotherapy, this may also happen with Caelyx.
Other side effects that may occur with a combination of Caelyx and bortezomib include:
-
joint pain, decreased or abnormal sensation to stimulation, inflammation of the cornea, redness
of the eye, redness of the scrotum.
39
-
you get reddening painful skin on your hands and feet,
When Caelyx is used alone, some of these effects are less likely to occur, and some have not occurred
at all.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
Strategies to prevent and treat hand-foot syndrome:
Every day for 4-7 days beginning immediately after you have received Caelyx:
-
soak hands and/or feet in basins of cold water when possible (e.g. while watching television,
reading, or listening to the radio);
-
keep hands and feet uncovered (no gloves, socks, etc.);
-
stay in cool places;
-
take cool baths during hot weather;
-
avoid vigorous exercise that might cause trauma to the feet (e.g. jogging);
-
avoid exposure of skin to very hot water (e.g. jacuzzis, saunas);
-
avoid tight fitting footwear or high-heeled shoes.
Pyridoxine (Vitamin B6):
-
Take 50-150 mg daily beginning at the first signs of redness or tingling.
5.
HOW TO STORE CAELYX
Keep out of the reach and sight 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 Caelyx after the expiry date which is stated on the label and carton.
Do not use Caelyx if you notice that it shows evidence of precipitation or any other particulate matter.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Caelyx contains
-
The active substance is doxorubicin hydrochloride. One ml of Caelyx 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 and sodium hydroxide.
Caelyx concentrate for solution for infusion: vials which provide 10 ml (20 mg) or 25 ml (50 mg).
What Caelyx looks like and contents of the pack
40
-
Vitamin B6 is available without prescription.
The solution for infusion is sterile, translucent and red. Caelyx is available in glass vials as a single
pack or packs of ten vials.
Not all pack sizes may be marketed.
Marketing Authorisation Holder:
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
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
Janssen-Cilag NV/SA
Antwerpseweg 15-17
B-2340 Beerse
Tél/Tel: +32 14 64 94 11
Luxembourg/Luxemburg
Janssen-Cilag NV/SA
Antwerpseweg 15-17
B-2340 Beerse
Tél/Tel: +32 14 64 94 11
България
Johnson & Johnson, d.o.o.
ж.к. Младост 4
Бизнес Парк София, сграда 4
София 1766
Тел.: +359 2 489 94 00
Magyarország
Janssen-Cilag Kft.,
Tó Park
H-2045 Törökbalint
Tel: +36 23 513 858
Česká republika
Janssen-Cilag s.r.o.
Karla Engliše 3201/6
CZ-150 00 Praha 5
Tel. +420 227 012 222
Malta
Am Mangion Ltd.
Mangion Building,
Triq Ġdida fi Triq Valletta
MT-LQA 6000 Luqa
Tel: +356 2397 6000
Danmark
Janssen-Cilag A/S
Hammerbakken 19
DK-3460 Birkerød
Tlf: +45 45 94 82 82
Nederland
Janssen-Cilag BV
Dr. Paul Janssenweg 150
NL-5026 RH Tilburg
Tel: +31 13 583 73 73
Deutschland
Janssen-Cilag GmbH
Johnson & Johnson Platz 1
D-41470 Neuss
Tel: +49 2137 955 955
Norge
Janssen-Cilag A.S.
Drammensveien 288
N-0283 Oslo
Tlf: +47 24 12 65 00
Eesti
Janssen-Cilag Polska Sp z o.o.
Eesti filiaal
Lõõtsa 2
EE-11415 Tallinn
Tel: +372 617 7410
Österreich
Janssen-Cilag Pharma GmbH
Vorgartenstraße 206b
A-1020 Wien
Tel: +43 1 610 300
Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Λεωφόρος Ειρήνης 56
GR-151 21 Πεύκη, Αθήνα
Polska
Janssen-Cilag Polska Sp. z o.o.
ul. Iłżecka 24
PL - 02-135 Warszawa
41
Tηλ: +30 210 80 90 000
Tel.+48 22 237 60 00
España
Janssen-Cilag, S.A.
Paseo de las Doce Estrellas, 5-7
E-28042 Madrid
Tel: +34 91 722 81 00
Portugal
Janssen-Cilag Farmacêutica, LDA.
Estrada Consiglieri Pedroso, 69 A
Queluz de Baixo
P-2734-503 Barcarena
Tel: +351 21 43 68 835
France
Janssen-Cilag
1, rue Camille Desmoulins, TSA 91003
F-92787 Issy Les Moulineaux, Cedex 9
Tél: +33 1 55 00 21 00
România
Johnson & Johnson d.o.o.
Str. Tipografilor nr. 11-15, Clădirea S-Park,
corp A2, etaj 5
Bucureşti 013714 - RO
Tel: +40 21 207 18 00
Ireland
Janssen-Cilag Ltd.
50 100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG - UK
Tel: +44 1494 567 567
Slovenija
Johnson & Johnson d.o.o.
Šmartinska 53
SI-1000 Ljubljana
Tel: +386 1 401 18 30
Ísland
Janssen-Cilag
c/o Vistor hf.
Hörgatún 2
IS-210 Garðabær
Sími: +354 535 7000
Slovenská republika
Janssen-Cilag
Pribinova 25, 5th floor
SK-811 09 Bratislava
Tel: +421 2 335 52 656
Italia
Janssen-Cilag SpA
Via M.Buonarroti, 23
I-20093 Cologno Monzese MI
Tel: +39 02 2510 1
Suomi/Finland
Janssen-Cilag OY
Vaisalantie/Vaisalavägen 2
FIN-02130 Espoo/Esbo
Puh/Tel: +358 207 531 300
Κύπρος
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ,
7 Ανδροκλέους
CY-1060 Λευκωσία
Τηλ: +357 22 755 214
Sverige
Janssen-Cilag AB
Box 7073
S-192 07 Sollentuna
Tel: +46 8 626 50 00
Latvija
Janssen-Cilag Polska Sp. z o.o. filiāle Latvijā
Matrožu iela 15
Rīga, LV 1048
Tel: +371 678 93561
United Kingdom
Janssen-Cilag Ltd.
50 100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG - UK
Tel: +44 1494 567 567
Lietuva
UAB “Johnson & Johnson”
Geležinio Vilko g. 18A
LT 08104 Vilnius
Tel: +370 5 278 68 88
42
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/
43
The following information is intended for medical or healthcare professionals only (see section 3):
Caution must be exercised in handling Caelyx solution. The use of gloves is required. If Caelyx comes
into contact with skin or mucosa, wash immediately and thoroughly with soap and water. Caelyx must
be handled and disposed of in a manner consistent with that of other anticancer medicinal products.
Determine the dose of Caelyx to be administered (based upon the recommended dose and the patient's
body surface area). Take the appropriate volume of Caelyx up into a sterile syringe. Aseptic technique
must be strictly observed since no preservative or bacteriostatic agent is present in Caelyx. The
appropriate dose of Caelyx must be diluted in 5 % (50 mg/ml) glucose solution for infusion prior to
administration. For doses < 90 mg, dilute Caelyx in 250 ml, and for doses ≥ 90 mg, dilute Caelyx in
500 ml.
To minimize 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 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.
It is recommended that the Caelyx 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.
44
Source: European Medicines Agency
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