Caelyx

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Doxorubicin hydrochloride 2 mg/mL (actual amount depends on total phosphate assay)
Available from:
Janssen-Cilag (New Zealand) Ltd
INN (International Name):
Doxorubicin hydrochloride 2 mg/mL (actual amount depends on total phosphate assay)
Dosage:
2 mg/mL
Pharmaceutical form:
Concentrate for infusion
Composition:
Active: Doxorubicin hydrochloride 2 mg/mL (actual amount depends on total phosphate assay) Excipient: Ammonium sulfate Carbamoyl-methoxypolyethylene glycol distearoyl glycerophosphoethanolamine sodium Cholesterol Histidine Lecithin Sucrose Water for injection
Units in package:
Vial, glass, single dose, 50mg/25ml, 1 dose unit
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Meiji Seika Kaisha Ltd
Therapeutic indications:
· Metastatic breast cancer in women for whom an anthracycline would be considered · Metastatic breast cancer in women who have failed a taxane-containing regimen
Product summary:
Package - Contents - Shelf Life: Vial, glass, single dose, 50mg/25ml - 1 dose units - 20 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) - Vial, glass, single dose, 20mg/10ml - 1 dose units - 20 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze)
Authorization number:
TT50-5796
Authorization date:
1996-04-04

CAELYX

pegylated liposomal doxorubicin hydrochloride

Consumer Medicine Information

What is in this leaflet

This leaflet answers some

common questions about

CAELYX. It does not contain all

the available information.

It does not take the place of

talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has

weighed the risks of you using

CAELYX against the benefits it is

expected to have for you.

If you have any concerns about

being given this medicine, ask

your doctor or pharmacist.

Keep this leaflet.

You may need to read it again.

What CAELYX is used

for

CAELYX is used to treat cancer of

the breast and ovary. It is used to

kill cancer cells, shrink the size

and delay the growth of the

tumour.

CAELYX is also used in

combination with another

medicine called bortezomib to

treat multiple myeloma, which is a

cancer of the plasma cell.

Plasma cells are produced in the

bone marrow and are a

component of the immune

system.

CAELYX is also used to treat

Kaposi’s Sarcoma, another type

of cancer. CAELYX produces an

improvement in Kaposi’s

Sarcoma including flattening,

lightening and shrinkage of the

cancer. Other symptoms of

Kaposi’s Sarcoma, such as

swelling around the tumour, may

also improve or disappear.

CAELYX belongs to a group of

medicines called antineoplastic or

cytotoxic medicines. You may

also hear of these being called

chemotherapy medicines.

CAELYX contains a medicine

called doxorubicin hydrochloride

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

liposomes which help to deliver

the medicine from the blood

stream to the cancerous tissue

rather than healthy normal tissue.

Your doctor, however, may

prescribe CAELYX for another

purpose.

Ask your doctor if you have any

questions about why CAELYX

has been prescribed for you.

Before you are given

CAELYX

When you must not be given it

Do not use CAELYX if you have

an allergy to CAELYX,

doxorubicin hydrochloride or

any of the ingredients listed at

the end of this leaflet.

Some of the symptoms of an

allergic reaction may include:

shortness of breath, wheezing,

difficulty breathing or a tight

feeling in your chest

swelling of the face, lips,

tongue or other parts of the

body

rash, itching, hives or flushed,

red skin.

Do not use CAELYX if you are

pregnant or breast-feeding.

Before you are given it

Your doctor must know about all

of the following before you are

given CAELYX.

Tell your doctor or pharmacist

if you have allergies to:

any medicines (including other

anti-cancer medicines)

any other substances, such as

foods, preservatives or dyes

Tell your doctor if you have or

have had any medical

conditions, especially the

following:

heart problems

liver problems

diabetes

recent surgery to remove your

spleen.

Tell your doctor if you have had

any or are on other anti-cancer

medicines.

Tell your doctor if you are

pregnant/planning to become

pregnant or breast-feeding.

CAELYX is not recommended in

pregnancy and breast-feeding.

Your doctor will discuss the

possible risks and benefits of

using CAELYX during pregnancy

and breast-feeding.

It is important that you or your

partner use a reliable method of

contraception to avoid

pregnancy during CAELYX

treatment and for 6 months

after treatment is stopped. This

applies to both female and male

patients on CAELYX treatment.

If you have not told your doctor

about any of the above, tell

CAELYX CMI 160512

Page 1 of 4

them before you are given

CAELYX.

Taking or being given other

medicines

Tell your doctor if you are

taking any other medicines,

including any that you buy

without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines may affect the

way other medicines work. Your

doctor or pharmacist will be able

to tell you what to do when being

given CAELYX with other

medicines.

How CAELYX is given

CAELYX is given by your doctor in

a drip (called an infusion) into a

vein. Depending on the dose this

may take from 30 minutes to

more than one hour.

Your doctor will decide how much

CAELYX you will be given and for

how long.

The usual dose for cancer of the

breast or ovary is 50 mg per

square metre of body surface

area. This dose is repeated every

four weeks for as long as the

disease does not progress and

you are able to tolerate the

treatment.

For multiple myeloma the usual

dose is 30 mg per square metre

of body surface area. This dose

is repeated every three weeks as

long as the disease has a

satisfactory response and you are

able to tolerate the treatment.

For Kaposi’s sarcoma the usual

dose is 20 mg per square metre

of body surface area. This dose

is repeated every 2 to 3 weeks for

2-3 months, then as often as

necessary to maintain an

improvement.

Overdose

As CAELYX is given to you

under the supervision of your

doctor, it is very unlikely that

you will receive too much.

However, if you experience any

side effects after being given

CAELYX, tell your doctor

immediately.

You may need urgent medical

attention.

Symptoms of a CAELYX

overdose include the side effects

listed below in the ‘Side Effects’

section, but are usually of a more

severe nature.

While you are using

CAELYX

Things you must do

If the drip stings or hurts while

you are receiving a dose of

CAELYX, tell your doctor

immediately.

If the medicine starts to upset

you or your symptoms become

worse, tell your doctor.

Be sure to keep all your

doctor’s appointments so your

progress can be checked.

Your doctor may want to check

your blood pressure and do some

blood and other tests from time to

time to check on your progress

and detect any unwanted side

effects.

Keep follow up appointments

with your doctor.

It is important to have your follow-

up doses of CAELYX at the

appropriate times to get the best

effects from your treatments.

Tell any other doctors, dentists,

and pharmacists who are

treating you that you are on

CAELYX treatment.

If you are about to be started

on any new medicine, tell your

doctor, dentist or pharmacist

that you are on CAELYX

treatment.

If you plan to have surgery that

needs a general anaesthetic,

tell your doctor or dentist that

you are on CAELYX treatment.

Tell your doctor, if you or your

partner become pregnant

during CAELYX treatment or 6

months after treatment is

stopped.

CAELYX can lower the number of

white blood cells and platelets in

your blood. This means that you

have an increased chance of

getting an infection or bleeding.

The following precautions should

be taken to reduce your risk of

infection or bleeding:

Avoid people who have

infections. Check with your

doctor immediately if you

think you may be getting an

infection, or if you get a

fever, chills, cough, hoarse

throat, lower back or side

pain or find it painful or

difficult to urinate.

Be careful when using a

toothbrush, toothpick or

dental floss. Your doctor,

dentist, nurse or pharmacist

may recommend other ways

to clean your teeth and

gums. Check with your

doctor before having any

dental work.

Be careful not to cut

yourself when you are using

sharp objects such as a

razor or nail cutters.

Avoid contact sports or

other situations where you

may bruise or get injured.

Things to be careful of

Be careful driving or operating

machinery until you know how

CAELYX affects you.

CAELYX may cause dizziness,

tiredness or sleepiness in some

people. Make sure you know how

CAELYX CMI 160512

Page 2 of 4

you react to CAELYX before you

drive a car, operate machinery, or

do anything else that could be

dangerous if you are light-headed

or sleepy.

Do not drive or operate

machinery, if you feel light-

headed or sleepy.

If you get reddening painful

skin on your hands and feet,

any heart problems or mouth

sores or if you develop a

temperature or any sign of an

infection while being given, or

soon after stopping CAELYX,

tell your doctor immediately.

Side Effects

Tell your doctor, nurse, or

pharmacist as soon as possible

if you do not feel well while you

are being given CAELYX.

All medicines can have side

effects. Sometimes they are

serious, most of the time they are

not. You may need medical

treatment if you get some of the

side effects.

Ask your doctor or pharmacist

to answer any questions you

may have.

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, low blood

pressure and possibly

dizziness and puffing of the

face.

stinging or swelling of the skin

at the site of injection may also

occur.

convulsions or fits.

Tell your doctor, nurse or

pharmacist if you notice any of

the above reactions or if the

drip stings or hurts while you

are receiving CAELYX.

Tell your doctor if you notice

any of the following and they

worry you. These are the more

common side effects of CAELYX:

general feeling of tiredness,

sleepiness or weakness

loss of appetite, weight loss

stomach pains, sickness

(nausea and vomiting),

diarrhoea, constipation

hair loss, skin rash

depression or anxiety

sore muscles or back pain

taste perversion

dark or pale areas of skin.

These are some of the more

common side effects of CAELYX.

Tell your doctor immediately if

you notice any of the following.

These are the more serious side

effects. You may need urgent

medical attention.

heart problems such as

irregular heart beat, shortness

of breath and/or swelling of

feet or hands

signs of frequent or worrying

infections such as fever,

severe chills, sore throat or

mouth ulcers, persistent

cough, pain/difficulty or

increased frequency of

passing urine, sore or red nose

bruising more easily than

normal

signs of anaemia, such as

tiredness, being short of

breath, and looking pale

redness, swelling and sores on

the palms of your hands and

feet

sores in the mouth, oral thrush

(a fungal infection in the

mouth), tongue inflammation

respiratory problems such as

difficulty in breathing which

may be linked to infections you

have caught as a result of your

disease

problems with vision, sore or

irritated eyes

feelings of pins and needles

pain, redness and dryness of

skin if previously experienced

during treatment with

radiotherapy may also happen

with CAELYX.

A few people may be allergic to

some medicines.

Tell your doctor or nurse

immediately if you notice any of

the following:

swelling of the face, lips,

mouth or throat which may

cause difficulty in swallowing

or breathing

shortness of breath

skin problems such as rash or

itchiness

pinkish, itchy swellings on the

skin, also called hives or nettle

rash

dizziness, light-headedness,

fainting.

If you have these, you may have

had a serious allergic reaction to

CAELYX. You may need urgent

medical attention.

Other side effects not listed above

may also occur in some patients.

Tell your doctor if you notice

any other effects.

Do not be alarmed by this list of

possible side effects. You may

not experience any of them.

After CAELYX has

been stopped

Tell your doctor immediately if

you notice any of the following

side effects, even if they occur

several weeks after stopping

treatment with CAELYX.

any heart problems such as

shortness of breath or irregular

heart beat

fever or any other sign of

infection

redness, swelling or sores on

the palms of hands and feet.

Tell your doctor if you notice

any other effects.

CAELYX CMI 160512

Page 3 of 4

Tell your doctor, if you or your

partner become pregnant

during the 6 months after

CAELYX treatment is stopped.

Storage

CAELYX will be stored in the

pharmacy or on the ward and

looked after by your doctor,

pharmacist or nurse.

This medicine is a concentrated

suspension for infusion and is

stored at 2

C to 8

C in the

refrigerator. Do not freeze.

Do not use CAELYX if the

expiry date (EXP) printed on the

pack has passed.

Product Description

What it looks like

CAELYX comes as a sterile,

translucent red suspension (2 mg

per 1 mL) in a glass vial. It is

available as 20 mg/10 mL or 50

mg/25 mL vials with one vial

inside each pack.

Ingredients

Active ingredient:

Pegylated liposomal doxorubicin

hydrochloride (2 mg per 1 mL)

Inactive ingredients:

sodium methoxy PEG-40-

carbonyl-

distearoylphosphatidyl-

ethanolamine (MPEG-DSPE)

hydrogenated soy

phosphatidylcholine (HSPC)

cholesterol

ammonium sulfate

sucrose

histidine

Water for Injections

hydrochloric acid

sodium hydroxide

Sponsor

JANSSEN-CILAG Pty Ltd

1-5 Khartoum Rd

Macquarie Park NSW 2113

Australia

Telephone: 1800 226 334

NZ Office: Auckland, New

Zealand

Telephone: 0800 800 806

Australian Registration

Number

CAELYX 20 mg/10 mL:

AUST R 60384

CAELYX 50 mg/25 mL:

AUST R 79921

This leaflet was prepared May

2016

CAELYX CMI 160512

Page 4 of 4

CCDS (181113)

CAELYX (190312) ADS

CAELYX

®

INJECTION

Doxorubicin hydrochloride

DATA SHEET

1. PRODUCT NAME

CAELYX

2 mg/mL concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One mL of CAELYX contains 2 mg doxorubicin hydrochloride in a pegylated liposomal

formation.

CAELYX,

pegylated

liposomal

formulation

doxorubicin

hydrochloride,

contains

doxorubicin encapsulated in liposomes having surface-bound methoxypolyethylene glycol

groups (pegylated liposomes). This process is known as pegylation and protects the

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. PHARMACEUTICAL FORM

Concentrate for solution for infusion

CAELYX is a concentrate for infusion presented as a sterile, translucent, red suspension with

a pH of 6.5.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

CAELYX is indicated for the treatment of:

Metastatic breast cancer in women for whom an anthracycline would be considered

Metastatic breast cancer in women who have failed a taxane-containing regimen

Advanced epithelial ovarian cancer in women who have failed a first-line platinum-based

chemotherapy regimen.

AIDS-related

Kaposi’s

sarcoma

(KS)

patients

with

counts

(<200 lymphocytes/mm3) and extensive mucocutaneous or visceral disease.

CAELYX

used

first-line

systemic

chemotherapy,

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 doxorubicin (or other anthracycline).

CAELYX is also indicated, 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.

CCDS (181113)

CAELYX (190312) ADS

4.2 Dose and method of administration

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 HCl.

Dose

Breast Cancer / Ovarian Cancer:

CAELYX 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.

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 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 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 over the next 15 minutes. If tolerated, the infusion was

completed over the next hour for a total infusion time of 90 minutes.

Subsequent CAELYX infusions may be administered over a 60 minute period.

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

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.

For doses < 90 mg: dilute CAELYX in 250 ml of 5 % (50 mg/ml) glucose solution for infusion.

For doses

90 mg: dilute CAELYX in 500 ml of 5 % (50 mg/ml) glucose solution for infusion.

The intravenous catheter and tubing should be flushed with 5 % glucose solution for infusion

between administration of CAELYX and bortezomib. 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. The first infusion of CAELYX should be administered over 90 minutes,

as follows:

10 ml over first 10 minutes

20 ml over next 10 minutes

40 ml over next 10 minutes

then, complete the infusion over a total of 90 minutes.

Subsequent doses of CAELYX will be administered over 1 hour, as tolerated. If an infusion

reaction to CAELYX occurs, stop the infusion and after the symptoms resolve, attempt to

administer the remaining CAELYX over 90 minutes, as follows:

10 ml over first 10 minutes

20 ml over next 10 minutes

40 ml over next 10 minutes

then, complete the remaining infusion over a total of 90 minutes.

CCDS (181113)

CAELYX (190312) ADS

Infusion may be given through a peripheral vein or a central line.

AIDS Related Kaposi’s Sarcoma:

CAELYX should be administered intravenously at 20 mg/m

every two-to-three weeks.

Intervals shorter than 10 days should be avoided as drug accumulation and increased toxicity

cannot be ruled out. Patients should be treated for two-to-three months to achieve a

therapeutic response. Treatment should be continued as needed to maintain a therapeutic

response. CAELYX, diluted in 250 mL 5% Glucose Intravenous Infusion, is administered by

intravenous infusion over 30 minutes.

All Patients:

If the patient experiences early symptoms or signs of infusion reaction (see section 4.4),

immediately discontinue the infusion, give appropriate premedications (antihistamine and/or

short acting corticosteroid) and restart at a slower rate.

Guidelines for CAELYX 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 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) (US).

The tables for PPE and stomatitis 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 hematologic 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 Adverse Reactions.

Table 1: PALMAR-PLANTAR ERYTHRODYSESTHESIA

Toxicity Grade at

Current Assessment

Week After Prior CAELYX Dose

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

Discontinue

CAELYX

CCDS (181113)

CAELYX (190312) ADS

Toxicity Grade at

Current Assessment

Week After Prior CAELYX Dose

Week 4

Week 5

Week 6

Grade 4

(diffuse or local process

causing infectious

complications, or a

bedridden state or

hospitalisation)

Wait an additional

week

Wait an additional

week

Discontinue

CAELYX

Table 2: STOMATITIS

Toxicity Grade at

Current Assessment

Week After Prior CAELYX Dose

Week 4

Week 5

Week 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,

oedema, or ulcers, but

cannot eat)

Wait an additional

week

Wait an additional

week

Discontinue

CAELYX

Grade 4

(requires parenteral or

enteral support)

Wait an additional

week

Wait an additional

week

Discontinue

CAELYX

Table 3: HAEMATOLOGICAL TOXICITY (ANC OR PLATELETS):

1.

MANAGEMENT OF PATIENTS WITH BREAST OR OVARIAN CANCER

GRADE

ANC

(x10

PLATELETS

(x10

/L)

MODIFICATION

Grade

1

1.5 - 1.9

75 - 150

Resume treatment with no dose reduction

Grade

2

1.0 - <1.5

50 - <75

Wait until ANC

1.5 x 10

/L and platelets

75 x10

/L; redose with no dose reduction

Grade

3

0.5 - <1.0

25- <50

Wait until ANC

1.5 x10

/L and platelets

75 x10

/L; redose with no dose reduction

Grade

4

<0.5

<25

Wait until ANC

1.5 x10

/L and platelets

75 x10

/L; decrease dose by 25% or

continue full dose with growth factor

support.

2.

MANAGEMENT OF PATIENTS WITH AIDS-KS

GRADE

ANC

(x10

PLATELETS

(x10

MODIFICATION

Grade 1

1.5 - 1.9

75 - 150

Resume treatment with no dose reduction

CCDS (181113)

CAELYX (190312) ADS

GRADE

ANC

(x10

PLATELETS

(x10

/L)

MODIFICATION

Grade 2

1.0 - <1.5

50 - <75

Grade 3

0.5 - <1.0

25- <50

Wait until ANC

1.0 x

and platelets

50 x

; redose with no dose reduction.

G-CSF (or GM-CSF) may be given as

concomitant therapy to support the blood

count when the ANC count is <1 x 10

Grade 4

<0.5

<25

For multiple myeloma patients treated with CAELYX in combination with bortezomib who

experience PPE or stomatitis, the CAELX dose should be modified as described in Table 1

and Table 2 above, respectively. For more detailed information on bortezomib dosing and

dosage adjustments, see the Prescribing Information 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

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

Haemoglobin < 8g/dL

ANC < 500/mm

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 haematologic

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-haematologic

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 PI for bortezomib

*for more information on bortezomib dosing and dosage adjustment, see the PI for bortezomib

Special Populations

Patients with impaired hepatic function:

Prior to CAELYX administration, hepatic function should be evaluated using conventional

clinical laboratory tests such as ALT/AST, alkaline phosphatase and bilirubin. In a small

number of patients with impaired hepatic function (bilirubin values up to 70 micromoles/L)

administered 20 mg/m

CAELYX, there appeared to be no change in the clearance and

terminal half-life of CAELYX. However, until further experience is gained, the CAELYX dosage

should be reduced in patients with impaired hepatic function, based on experience from the

breast and ovarian clinical trial programs as follows:

At initiation of therapy, if the bilirubin is between 20 – 51 micromoles/L, the first dose is reduced

by 25%. If the bilirubin is > 51 micromoles/L, 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

CCDS (181113)

CAELYX (190312) ADS

bilirubin and liver enzymes up to 4 x the upper limit of the normal range. No data are available

for patients with severe hepatic impairment.

Patients with impaired renal function:

As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should

not be required with CAELYX. Population-based analysis confirms that changes in renal

function over the range tested (estimated creatinine clearance 30-156 mL/min) do not alter

the pharmacokinetics of CAELYX. 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 with splenectomy, treatment with CAELYX

is not recommended.

Paediatric patients:

The safety and effectiveness in patients less than 18 years of age have not been established.

Elderly patients:

Population based analysis demonstrates that age across the range tested (21–75 years) does

not significantly alter the pharmacokinetics of CAELYX.

Method of administration

Caelyx is administered as an intravenous infusion.

CAELYX MUST NOT BE GIVEN BY THE INTRAMUSCULAR OR SUBCUTANEOUS ROUTE

(see section 6.6).

DO NOT administer 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% Glucose Intravenous Infusion 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.

For further instructions on preparation and special precautions for handling see section 6.6.

4.3 Contraindications

CAELYX is contraindicated in patients who have a history of hypersensitivity reactions

to its components or to doxorubicin HCl.

CAELYX should not be administered during pregnancy or while breast feeding.

CAELYX should not be used to treat AIDS-KS that may be effectively treated with local

therapy or systemic alfa-interferon.

4.4 Special warnings and precautions for use

For common adverse events which required dose modification or discontinuation see section

4.8.

Cardiac Risk

Experience with CAELYX at high cumulative doses is too limited to have established its effects

on the myocardium (see section 4.8). Moreover, the long-term cardiac effects of CAELYX

relative to the conventional formulation of doxorubicin HCl have not been adequately

evaluated. Until further clinical data are available, the risk of developing cardiomyopathy is

assumed to be similar to that of standard doxorubicin.

All patients receiving CAELYX should routinely undergo frequent ECG monitoring.

CCDS (181113)

CAELYX (190312) ADS

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,

most

definitive

test

anthracycline

myocardial

injury,

i.e.

endomyocardial biopsy, should be considered.

More specific methods for evaluation and monitoring of cardiac functions as compared to ECG

are a measurement of left ventricular ejection fraction by echocardiography or preferably by

multiple gated angiography (MUGA). These methods should be applied routinely before the

initiation of CAELYX and should be repeated periodically during treatment. In a phase-III

clinical trial comparing CAELYX (50 mg/m

every 4 weeks) versus doxorubicin (60 mg/m

every 3

weeks),

risk of developing a

cardiac event

a function of

cumulative

anthracycline dose was significantly lower with CAELYX than with doxorubicin (HR=3.16,

p<0.001). At cumulative doses between 450 mg/m

and 600 mg/m

there was no increased

risk of cardiac toxicity with CAELYX. The evaluation of left ventricular function is considered

to be mandatory before each additional dose of CAELYX which exceeds a lifetime cumulative

dose of anthracyclines (e.g., Adriamycin) of 600 mg/m

The evaluation tests and methods mentioned above concerning the monitoring of cardiac

performance during anthracycline therapy should 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.

Caution should be exercised in patients with impaired cardiac function who receive CAELYX.

Whenever

cardiomyopathy

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 should be observed in patients who have received other anthracyclines. The total

dose of doxorubicin HCl should also take into account any previous (or concomitant) therapy

with

cardiotoxic

compounds

such

other

anthracyclines/anthraquinones

e.g.,

5-Fluorouracil. Cardiac toxicity also may occur at cumulative anthracycline doses lower than

450 mg/m

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

) is similar to the 20 mg/m

profile in patients with AIDS-KS.

Myelosuppression

Many patients treated with CAELYX have baseline myelosuppression due to such factors as

their 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

myelosuppression was generally mild to moderate, reversible, and was not associated with

episodes of neutropenic 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 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 should be performed frequently during the course of CAELYX, and at a

minimum, prior to each dose of CAELYX.

CCDS (181113)

CAELYX (190312) ADS

Persistent myelosuppression, although not seen in patients with breast or ovarian cancer, 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.

Given the difference in pharmacokinetic profiles and dosing schedules, CAELYX should not

be used interchangeably with other formulations of doxorubicin hydrochloride.

Combination therapy with CAELYX has been extensively studied in solid tumour populations.

CAELYX has been safely co-administered with standard doses of chemotherapeutic agents

that are frequently used in the treatment of advanced breast cancer or ovarian cancer,

however the efficacy of such combination regimens has not been established.

Infusion-associated Reactions

Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-

like or anaphylactoid-like reactions, may occur within minutes of starting the infusion of

CAELYX. Symptoms include asthma, flushing, urticarial rash, chest pain, fever, hypertension,

tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, headache, 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).

Palmar-plantar Erythrodysesthesia

Palmar-plantar erythrodysesthesia (PPE) is characterised by painful, red macular and/or

papular bullous skin eruptions. In patients experiencing this event, it is generally seen after

two or three cycles of treatment. In most patients it clears in one or two weeks, with or without

treatment with corticosteroids. Pyridoxine at a dose of 50-150 mg per day has been used for

the prophylaxis and treatment of PPE. 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). It appears to be dose- and schedule-related and can be reduced by

extending the CAELYX dose interval 1-2 weeks or reducing the CAELYX dose (see section

4.2). This reaction can be severe and debilitating in some patients, however, and may require

discontinuation of treatment.

Extravasation Injury

Although local necrosis following extravasation has been reported very rarely, CAELYX should

be considered an irritant. Although animal studies indicate that the administration of

doxorubicin HCl as a liposomal formulation reduces the potential for extravasation injury, the

possibility of doxorubicin-related skin injury exists, and care should be taken to avoid

extravasation of CAELYX. If any signs or symptoms of extravasation occur (e.g. stinging,

erythema) the infusion should be immediately terminated and restarted 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

skin

reaction

prior

radiotherapy

rarely

occurred

with

CAELYX

administration.

CCDS (181113)

CAELYX (190312) ADS

Diabetic Patients

It should be noted that each vial of CAELYX contains sucrose and is administered in

5% Glucose Intravenous Infusion.

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 or those receiving a cumulative CAELYX dose greater

than 720 mg/m

. Cases of secondary oral cancer were diagnosed both, during treatment with

CAELYX, 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.

4.5 Interactions with other medicines and other forms of interaction

No formal drug interaction studies have been conducted with CAELYX, although phase II

combination trials with conventional chemotherapy agents have been conducted in patients

with gynaecological malignancies. Caution should be exercised in the concomitant use of

drugs known to interact with doxorubicin HCl. Although not formally studied, CAELYX, like

other doxorubicin HCl preparations, may potentiate the toxicity of other anti-cancer therapies.

In patients with solid tumours (including breast and ovarian cancer) who received concomitant

cyclophosphamide or taxanes, no new additive toxicities were noted. In patients with AIDS-

KS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of

the hepatotoxicity of 6-mercaptopurine have been reported with doxorubicin HCl. Caution

should be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at

the same time.

4.6 Fertility, pregnancy and lactation

Pregnancy

Category D. CAELYX is embryotoxic at doses of 1 mg/kg/day in rats (about 1/3 the

recommended human dose on a mg/m2 basis). CAELYX is embryotoxic and abortifacient at

0.5 mg/kg/day in rabbits (about ¼ the recommended human dose on a mg/m2 basis).

Embryotoxicity was characterised by increased embryo-foetal deaths and reduced litter sizes.

There are no adequate and well-controlled studies in pregnant women. If CAELYX is to be

used during pregnancy, or if the patient becomes pregnant during therapy, the patient should

be apprised of the potential hazard to the foetus and such treatment should only proceed with

the patient’s complete informed consent.

Women of child-bearing potential

Women of childbearing potential should be advised to avoid pregnancy while they or their

male partner are receiving CAELYX and in the six months following discontinuation of

CAELYX therapy.

Breastfeeding

It is not known whether this drug is excreted in human milk and because of the potential for

serious adverse reactions in nursing infants from CAELYX, mothers should discontinue

nursing prior to taking this drug. Health experts recommend that HIV-infected women do not

breast-feed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects on the ability to drive and use machines

Although CAELYX should not affect driving performance, in studies to date, dizziness and

somnolence were associated infrequently (

5%) with the administration of CAELYX. Patients

who suffer from these effects should avoid driving and operating machinery.

CCDS (181113)

CAELYX (190312) ADS

4.8 Undesirable effects

Breast Cancer Patients (Dosage: 50mg/m

2

)

254 patients with advanced breast cancer who had not received prior chemotherapy for

metastatic disease were treated with CAELYX at a dose of 50 mg/m

every 4 weeks in a

phase III clinical trial (I97-328). The most frequently reported treatment related adverse effects

included palmar-plantar erythrodysesthesia (PPE) (48.0 %) and nausea (37.0 %) (see Table

5). These effects were mostly mild and reversible, with severe (Grade III) cases reported in

17.0 % and 3.0 % respectively, and no reported incidences of life threatening (Grade IV) cases

for either PPE or nausea. Infrequently, these effects resulted in permanent treatment

discontinuation (7.0 % and 0 % respectively). Pronounced alopecia (or total hair loss) was

seen in only 7.0 % of CAELYX-treated patients as compared with 54.0 % of patients treated

with doxorubicin.

Haematologic adverse effects were infrequently reported and were mostly mild or moderate

in severity and manageable. Anaemia, neutropenia, leucopenia and thrombocytopenia were

infrequently reported at incidences of 5.0 %, 4.0 %, 2.0 %, and 1.0 %, respectively. Life

threatening (Grade IV) haematologic effects were reported at incidences of < 1.0 %. The need

for either growth factor support or transfusion support was minimal (5.1 % and 5.5 % of

patients, respectively).

Clinically significant laboratory abnormalities (Grades III and IV) in this breast cancer group

included increases in total bilirubin (2.4 %) and AST (1.6 %). Increases in ALT were less

frequent

(< 1 %).

Clinically

significant haematologic

measurements

were

infrequent as

measured

leucopenia

(4.3 %),

anaemia

(3.9 %),

neutropenia

(1.6 %)

thrombocytopenia (1.2 %). Sepsis was reported at an incidence of 1 %. No clinically significant

increases in serum creatinine were reported.

In 150 patients with advanced breast cancer who had failed a prior first or second line taxane-

containing chemotherapy regimen and were subsequently treated with CAELYX at a dose of

50 mg/m

every 4 weeks in a phase III clinical trial (C/I96-352), the safety profile was

consistent with that reported for CAELYX in previous studies using the same dosage regimen

(see Table 5).

The proportion of

patients

experiencing

clinically

significant

laboratory

abnormalities was low and comparable numerically to the 254 breast cancer patients receiving

CAELYX as first-line therapy, with the exception of leucopenia (20 %).

Table 5. Treatment Related Undesirable Effects Reported in Breast Cancer Clinical Trials

(I97-328 and C/I96-352) (

5 % of CAELYX-treated patients) by Severity, Body

System and Preferred Term

AE by body system

I97-328

All Severities

%

I97-328

Grades III/IV

%

C/I96-352

All Severities

%

C/I96-352

Grades III/IV

%

Autonomic Nervous

System

Flushing

< 1

< 1

Body as a whole

Asthenia

Erythema

< 1

Fatigue

< 1

Fever

< 1

Weakness

< 1

Weight Decrease

< 1

Gastro-intestinal system

Abdominal Pain

< 1

Anorexia

Constipation

< 1

Diarrhoea

< 1

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