Camptosar

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Irinotecan hydrochloride trihydrate 20 mg/mL;  ;  
Available from:
Pfizer New Zealand Limited
INN (International Name):
Irinotecan hydrochloride trihydrate 20 mg/mL
Dosage:
20 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Irinotecan hydrochloride trihydrate 20 mg/mL     Excipient: Hydrochloric acid Lactic acid Sodium hydroxide Sorbitol Water for injection
Units in package:
Vial, glass, 2 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Olon SpA
Product summary:
Package - Contents - Shelf Life: Vial, glass, - 2 mL - 36 months from date of manufacture stored at or below 30°C protect from light - Vial, glass, - 5 mL - 36 months from date of manufacture stored at or below 30°C protect from light - Vial, plastic, Polypropylene - 2 mL - 36 months from date of manufacture stored at or below 30°C protect from light - Vial, plastic, Polypropylene - 5 mL - 36 months from date of manufacture stored at or below 30°C protect from light - Vial, plastic, Polypropylene - 15 mL - 36 months from date of manufacture stored at or below 30°C protect from light
Authorization number:
TT50-5856
Authorization date:
1996-08-30

CAMPTOSAR

CAMPTOSAR

®

Irinotecan hydrochloride

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about CAMPTOSAR.

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 treating you with

CAMPTOSAR against the expected

benefits it will have for you.

Ask your doctor if you have any

concerns about being treated with

this medicine.

Keep this leaflet.

You may need to read it again.

What CAMPTOSAR is

used for

CAMPTOSAR is used to treat bowel

cancer which has spread to other

parts of the body. Cancer which has

spread cannot be treated by surgery

alone. One of the options in this

situation is treatment with an

anticancer medicine, known as

chemotherapy.

CAMPTOSAR may be used once

spread of cancer beyond the bowel is

first diagnosed. At this time

CAMPTOSAR will be given in

combination with other anticancer

medicines. Alternatively,

CAMPTOSAR is used alone when

the cancer has not responded or has

returned after initial treatment.

Ask your doctor if you have any

questions about why

CAMPTOSAR has been

prescribed for you.

Your doctor may have prescribed it

for another purpose.

Use in children

It is not known if CAMPTOSAR is

safe and effective in the treatment of

children.

Before being treated

with CAMPTOSAR

When CAMPTOSAR must

not be given

CAMPTOSAR must not be given if

you:

are allergic to irinotecan

hydrochloride or any of the

ingredients listed at the end of

this leaflet

are or may become pregnant

are breastfeeding or intend to

breastfeed.

Before treatment with

CAMPTOSAR

You should be treated with

CAMPTOSAR by a doctor who is

experienced in treating patients with

cancer. Treatment will normally take

place in a hospital because of the

need for hospital facilities and skilled

personnel.

It is likely that your doctor will give

you one or more medicines before

administering CAMPTOSAR, to help

stop you vomiting or feeling sick

after the treatment. You will

probably also have a blood test

before each treatment.

You should tell your doctor if:

you are 65 years of age or older

you have or have had liver

disease, kidney disease or heart

disease

you have previously been treated

with radiation therapy

you have diabetes

you have asthma

you have constipation

you have difficulty urinating

you have hereditary fructose

intolerance

you have Crigler-Najjar

syndrome or Gilbert's syndrome

you are going to be vaccinated

(have an injection to prevent a

certain disease).

If you have not told your doctor

about any of the above, tell your

doctor before you are given

CAMPTOSAR.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including:

all prescription medicines

all medicines, vitamins, herbal

supplements or natural therapies

you buy without a prescription

from a pharmacy, supermarket,

naturopath or health food shop.

Some medicines and CAMPTOSAR

may interfere with each other. In

particular, tell your doctor if you are

taking:

laxatives (e.g. for constipation)

CAMPTOSAR

diuretics (medicines which make

you pass urine more frequently

e.g. for heart disease)

any medicine for nausea or

diarrhoea

dexamethasone (may be used to

treat skin diseases, asthma or

other allergic disorders)

anticonvulsants, used to treat

seizures

St John's Wort, a herbal medicine

used to treat depression

ketoconazole, used to treat fungal

infections

atazanavir, used to treat HIV-1

infection

prochlorperazine, used to treat

nausea, vomiting and dizziness

suxamethonium or other

medicines used as an anaesthetic

other medicines used to treat

cancer.

Ask your doctor or other health

care professional if you are not

sure about this list of medicines.

You may need to take different

amounts of your medicines or you

may need to use different medicines.

Your doctor will advise you.

How CAMPTOSAR is

given

CAMPTOSAR will be given to you

by your doctor. It is diluted and

given by slow infusion into a vein

over a period of 90 minutes.

It is recommended that

CAMPTOSAR be given in different

treatment courses depending on

whether CAMPTOSAR is given

alone or in combination with other

anticancer medicines.

Combination Treatment Courses

When CAMPTOSAR is given in

combination, treatment courses are of

6 weeks' duration given either

weekly or fortnightly. Rest periods

of 1 or 2 weeks are incorporated into

the 6 week courses.

Single Treatment Courses

CAMPTOSAR may be given either

weekly for 4 weeks followed by a 2

week rest period or it may be given

once every 3 weeks.

Depending on your response,

treatment courses may be repeated

more than once.

It is recommended that treatment

with CAMPTOSAR should be

interrupted if you get severe

diarrhoea or other intolerable side

effects.

Dose

Your doctor will decide the most

appropriate dose of CAMPTOSAR to

be given.

Ask your doctor if you want more

information about the dose of

CAMPTOSAR and the other

medicines you will be receiving and

how they are given while you are

being treated with CAMPTOSAR.

After your first treatment course, the

dose of CAMPTOSAR may be

increased by your doctor if you have

not had too many side effects.

Your doctor will lower the dose or

stop treatment if you have serious

side effects, particularly diarrhoea or

changes appearing in your blood

tests.

In case of overdose

Overdose is unlikely as treatment

will be given in hospital under the

supervision of a doctor. The possible

effects of overdose are the same as

those listed below under Side effects.

Tell your doctor immediately if

you do not feel well while being

given CAMPTOSAR.

While being treated

with CAMPTOSAR

Things you must do

Keep all appointments with your

doctor and always discuss with

your doctor any problems during

or after treatment with

CAMPTOSAR.

Tell your doctor as soon as possible

if diarrhoea occurs.

Diarrhoea is a common side effect of

CAMPTOSAR. If untreated, severe

diarrhoea can be life-threatening.

Your doctor will prescribe

loperamide (a medicine to treat

diarrhoea) for you to take in case you

get diarrhoea after treatment. You

should start taking loperamide, when

you first have poorly formed or loose

stools or have more frequent bowel

movements than you would normally

expect.

You must tell your doctor if you

cannot get diarrhoea under control

within 24 hours after taking

loperamide.

You should not take loperamide for

more than 48 hours.

Also tell your doctor if you develop

a fever in addition to the

diarrhoea.

In these cases, your doctor may give

you antibiotics. If the diarrhoea or

fever persists you may become

dehydrated and need to go to

Accident and Emergency at your

nearest hospital for treatment.

You may need to take antibiotics if

there are changes in your blood tests

indicating a lack of white blood cells.

Symptoms of this may include

frequent infections such as fever,

severe chills, sore throat or mouth

ulcers. If this persists, you may need

to go to Accident and Emergency at

your nearest hospital for treatment.

If you have severe stomach cramps

you may need to be treated with

antibiotics.

You must use a reliable method of

contraception (birth control) while

CAMPTOSAR

being treated with CAMPTOSAR.

If pregnancy occurs, consult your

doctor.

Things you must not do

Because of the risk of diarrhoea,

do not take laxatives during

treatment courses with

CAMPTOSAR.

Talk to your doctor if you need more

information about this.

Do not start taking any other

medicines, prescription or not,

without first telling your doctor or

pharmacist.

Side effects

CAMPTOSAR, like all other

medicines, may cause unwanted side

effects. Side effects are very

common with anti-cancer medicines

such as CAMPTOSAR and they may

be severe. Deaths have occurred

which, in some cases, may have been

related to treatment.

Tell your doctor immediately if

you get any of the following side

effects:

diarrhoea

start to vomit

develop a fever or any type of

infection

fainting, light-headedness or

dizziness

bloody or black stools

cannot eat or drink due to nausea

or vomiting.

The above side effects may be

serious. You may need urgent

medical attention.

Very common side effects (occurring

in over 50% of patients) are:

diarrhoea or stomach cramps;

may occur early (during or

shortly after a treatment) or late

(usually more than 24 hours after

treatment)

nausea, vomiting, loss of appetite

anaemia, which may make you

weak and light-headed or may

cause you to faint

increased risk of infections

including severe infections

weakness

hair loss.

Common side effects (occurring in

10-50% of patients) are:

constipation, flatulence (passing

wind), sore mouth, heartburn

fever (increased body

temperature), chills, headache,

back pain or other types of pain,

infection, fluid retention which

results in swelling

weight loss, dehydration

runny nose or eyes, increased

saliva, sweating or flushing

skin rash

coughing, difficulty breathing

difficulty sleeping or dizziness.

Less common side effects (occurring

in less than 10% of patients) are:

increased risk of bleeding

severe fever associated with a

reduction in white blood cell

numbers

bleeding from the bowel

jaundice (yellowing of skin and

eyes)

severe breathing difficulties

generally feeling unwell

abnormal manner of walking

fungal infections (e.g. thrush)

kidney problems

problems speaking.

In addition to the above side effects

the following have also been

reported:

allergic reactions; some of the

symptoms of an allergic reaction

may include: rash, itching or

hives on the skin. In more severe

cases symptoms may also include

shortness of breath, wheezing or

difficulty breathing, swelling of

the face, lips, tongue or other

parts of the body

pins and needles

bloating or pain in upper stomach

chest pains

hiccups.

Other side effects not listed above

may happen in some people. Some

of these side effects can only be

found when your doctor does tests to

check your progress.

Rare side effects of CAMPTOSAR

have also been reported. These

include effects on the heart and blood

vessels such as:

slowed heart beat

fainting

blackouts

blood clots

swelling and redness along a

vein, which is extremely tender

when touched

chest pains

heart attack

stroke.

Your doctor has information on

monitoring for such side effects and

their treatment. A very small number

of patients have died suddenly while

on CAMPTOSAR.

Tell your doctor as soon as possible

if you experience any side effects,

including any effects not listed

above.

After treatment with

CAMPTOSAR

Storage

CAMPTOSAR will normally be

stored in a hospital. It should be

stored below 30°C and should be

protected from light (kept in the

packaging before use).

CAMPTOSAR must never be frozen.

CAMPTOSAR

Product description

What it looks like

CAMPTOSAR is a sterile, clear,

light yellow, solution in a vial. Each

vial is for single use only and is

contained in an outer carton.

Ingredients

The active ingredient in

CAMPTOSAR is irinotecan

hydrochloride. There is 20 mg of

irinotecan hydrochloride in each

1 mL of CAMPTOSAR injection.

CAMPTOSAR also contains:

sorbitol

lactic acid

Water for Injections.

It might also contain sodium

hydroxide or hydrochloric acid.

Supplier

CAMPTOSAR is supplied in

Australia by:

Pfizer Australia Pty Ltd

ABN 50 008 422 348

38-42 Wharf Road

West Ryde NSW 2114

Toll Free Number 1800 675 229.

CAMPTOSAR is supplied in New

Zealand by:

Pfizer New Zealand Ltd

PO Box 3998

Auckland

Toll Free Number: 0800 736 363.

Australian Registration

Numbers

40 mg/2 mL: AUST R 58807

(not currently supplied)

100 mg/5 mL: AUST R 58806

(not currently supplied)

300 mg/15 mL: AUST R 146909.

Date of preparation

This leaflet was revised in September

2014.

© Pfizer Australia Pty Ltd 2014.

® = Registered trademark

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NEW ZEALAND DATA SHEET

1. PRODUCT NAME

CAMPTOSAR® Injection: Irinotecan hydrochloride injection 20 mg/mL.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of CAMPTOSAR Injection contains 20 mg irinotecan hydrochloride.

Excipient(s) with known effects:

Sorbitol

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

CAMPTOSAR injection is supplied as a sterile, light yellow or pale yellow, clear, aqueous

solution with pH 3.5. It is intended for dilution with 5% Glucose Injection or 0.9% Sodium

Chloride Injection prior to infusion.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

CAMPTOSAR is indicated for the first line treatment of patients with metastatic carcinoma

of the colon or rectum, in combination with 5FU/leucovorin. CAMPTOSAR is also

indicated for patients with metastatic carcinoma of the colon or rectum whose disease has

recurred or progressed following initial therapy.

4.2 Dose and method of administration

It is recommended that patients receive premedication with antiemetic agents. Prophylactic

or therapeutic administration of atropine should be considered in patients experiencing

cholinergic symptoms (see section 4.4).

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Combination Agent Therapy

Dosage Regimens

CAMPTOSAR injection in Combination with 5-Fluorouracil (5-FU) and Leucovorin (LV)

CAMPTOSAR should be administered as an intravenous infusion over 90 minutes (see

Preparation of Infusion Solution). For all regimens, the dose of LV should be administered

immediately after CAMPTOSAR, with the administration of 5-FU to follow immediately

after the administration of LV. The recommended regimens are shown in Table 1.

Table 1: Combination Agent Dosage Regimens and Dose Modifications

a

Regimen 1

6 week cycle.

Treatment resumes Day 43

CAMPTOSAR

5-FU

125 mg/m

IV over 90 min on Day 1, 8, 15, 22, then 2 wk rest

20 mg/m

IV bolus injection Day 1, 8, 15, 22, then 2 wk rest

500mg/m

IV bolus injection Day 1, 8, 15, 22 then 2 wk rest

Starting dose and modified dose levels

b

(mg/m

2

)

Starting dose

Dose level 1

Dose level 2

CAMPTOSAR

5-FU

Regimen 2

6 week cycle.

Treatment resumes Day 43

CAMPTOSAR

5-FU Bolus

5-FU Infusion

180 mg/m

IV over 90 min on Day 1, 15, 29 then 1 wk rest

200 mg/m

IV over 2 hr on Day 1, 2, 15, 16, 29, 30 then 1 wk rest

400 mg/m

IV on Day 1, 2, 15, 16, 29, 30 then 1 wk rest

600 mg/m

IV over 22 hr on Day 1, 2, 15, 16, 29, 30 then 1 wk

rest

Starting dose and modified dose levels

b

(mg/m

2

)

Starting dose

Dose level 1

Dose level 2

CAMPTOSAR

5-FU Bolus

5-FU Infusion

Dose reductions beyond dose level –2 by decrements of

20% may be warranted for patients continuing to

experience toxicity. Provided intolerable toxicity does not develop, treatment with additional courses may

be continued indefinitely as long as patients continue to experience clinical benefit.

See Table 2.

Infusion follows bolus administration.

Dose Modifications

Patients should be carefully monitored for toxicity and assessed prior to each treatment,

especially during the first cycle of therapy. Doses of CAMPTOSAR and 5-FU should be

modified as necessary to accommodate individual patient tolerance to treatment. Based on

the recommended dose levels described in Table 1, subsequent doses should be adjusted as

suggested in Table 2, which shows the recommended dose modifications for combination

schedules. All dose modifications should be based on the worst preceding toxicity.

Patients should be diarrhoea free (return to pre-treatment bowel function) without requiring

antidiarrhoeal medications for at least 24 hours before receiving the next chemotherapy

administration.

A new course of therapy should not begin until the toxicity has recovered to NCI Grade 1 or

less, the granulocyte count has recovered to ≥1.5 x 10

/L, the platelet count has recovered to

≥100 x 10

/L, and treatment-related diarrhoea is fully resolved. Treatment should be

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delayed for 1 to 2 weeks to allow recovery from treatment-related toxicity. If the patient

has not recovered after a 2 week delay, consideration should be given to discontinuing

therapy. Provided intolerable toxicity does not develop, treatment with additional courses

of CAMPTOSAR/5-FU/LV may be continued indefinitely as long as patients continue to

experience clinical benefit.

Table 2: Recommended dose modifications during a course of therapy with the

CAMPTOSAR/5-FU/LV combination and at the start of each subsequent course of

therapy

Toxicity

NCI CTC Grade

During a Course of Therapy

At the Start of Subsequent

Courses of Therapy

No toxicity

Maintain dose level

Maintain dose level

Neutropenia

Maintain dose level

Decrease by 1 dose level

Omit dose, until resolved to

Grade



then decrease

by 1 dose level

Omit dose until resolved to

Grade



then decrease by

2 dose levels

Maintain dose level

Maintain dose level

Decrease by 1 dose level

Decrease by 2 dose levels

Neutropenic fever

Omit dose until resolved, then decrease by 2 dose levels.

Other

haematological

toxicities

Dose modifications for leucopenia or thrombocytopenia during a course of therapy and

at the start of subsequent courses of therapy are also based on NCI toxicity criteria and

are the same as recommended for neutropenia above.

Diarrhoea

Delay dose until resolved to baseline, then give same

dose

Omit dose until resolved to baseline, then decrease by 1

dose level

Omit dose until resolved to baseline, then decrease by 1

dose level

Omit dose until resolved to baseline, then decrease by 2

dose levels

Maintain dose level

Maintain dose level

Decrease by 1 dose level

Decrease by 2 dose levels

Other non-haematological toxicities

Maintain dose level

Omit dose until resolved to

Grade 1, then decrease by

1 dose level

Omit dose until resolved to

Grade 2, then decrease by

1 dose level

Omit dose until resolved to

Grade 2, then decrease by

2 dose levels

Maintain dose level

Maintain dose level

Decrease by 1 dose level

Decrease by 2 dose levels

Severity of adverse events based on NCI CTC (version 2.0) see http://ctep.info.nih.gov/CTC3/default.htm.

Relative to the starting dose used in the previous course.

For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR.

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Single Agent Therapy

Dosage Regimens

CAMPTOSAR should be administered as an intravenous infusion (see Preparation of

Infusion solution) over 90 minutes in a recommended weekly or once every 3 week dosage

schedule as shown below in Table 3.

Table 3: Single-Agent Regimens of CAMPTOSAR and Dose Modifications

Weekly regimen

6 week cycle

Treatment resumes Day 43

125 mg/m

IV over 90 mins Day 1, 8, 15, 22 then 2 week rest

Starting dose and modified dose levels

(mg/m

Starting Dose

Dose Level 1

Dose Level 2

Once every 3 week regimen

350 mg/m

IV over 90 mins once every 3 weeks

Starting dose and modified dose levels

(mg/m

Starting Dose

Dose Level 1

Dose Level 2

Subsequent doses may be adjusted as high as 150 mg/m

or as low as 50 mg/m

in 25 to 50 mg/m

decrements depending on individual patient tolerance.

Subsequent doses may be adjusted as low as 200 mg/m

in 50 mg/m

decrements depending on

individual patient tolerance.

See Table 5.

A reduction in the starting dose by one level of CAMPTOSAR may be considered for

patients with any of the following circumstances: over 65 years, prior pelvic/abdominal

radiotherapy,

performance

status

moderately

increased

bilirubin

levels

(17-34 µmol/L).

Patients with Impaired Hepatic Function (Single Agent)

In patients with hepatic dysfunction, the following starting doses are recommended:

Table 4: Starting Doses in Patients with Hepatic Dysfunction – Single Agent Regimens

Regimen

Serum Total Bilirubin

Concentration

Serum ALT/AST

Concentration

Starting Dose, mg/m

2

Single – Agent Weekly

1.5–3.0 x IULN

≤5.0 x IULN

3.1–5.0 x IULN

≤5.0 x IULN

<1.5 x IULN

5.1–20.0 x IULN

1.5–5.0 x IULN

5.1–20.0 x IULN

Single Agent Once

Every 3 Weeks

1.5–3.0 x IULN

>3.0 x IULN

Not recommended

a The safety and pharmacokinetics of CAMPTOSAR given once every 3 weeks have not been defined in

patients with bilirubin >3.0 x IULN and this schedule cannot be recommended in these patients.

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Dose Modifications

Patients should be carefully monitored for toxicity and doses of CAMPTOSAR should be

modified as necessary to accommodate individual patient tolerance to treatment. Based on

recommended dose-levels described in Tables 3 and 4, subsequent doses of CAMPTOSAR

should be adjusted as suggested in Table 5. All dose modifications should be based on the

worst preceding toxicity.

A new cycle of therapy should not begin until the toxicity has recovered to NCI Grade 1 or

less, the granulocyte count has recovered to ≥1.5 x 10

/L, the platelet count has recovered to

≥100 x 10

/L, and treatment-related diarrhoea is fully resolved. Treatment may be delayed

for 1 to 2 weeks to allow recovery from treatment-related toxicity. If the patient has not

recovered,

consideration

should

given

discontinuing

CAMPTOSAR

therapy.

Provided

intolerable

toxicity

does

develop,

treatment

with

additional

cycles

CAMPTOSAR may be continued indefinitely as long as patients continue to experience

clinical benefit.

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Table 5: Recommended dose modifications for single agent regiments

Toxicity

Grade

During a cycle

of therapy

At The Start Of Subsequent Cycle Of Therapy

Weekly

Weekly

Once Every 3 Weeks

No Toxicity

Maintain dose level

Increase by 1 dose level

up to a maximum dose

of 150 mg/m

Maintain dose level

Neutropenia

Maintain dose level

Decrease by 1 dose level

Omit dose until resolved to ≤Grade

2, then decrease by 1 dose level

Omit dose until resolved to ≤Grade

2, then decrease by 2 dose levels

Maintain dose level

Maintain dose level

Decrease by 1 dose

level

Decrease by 2 dose

levels

Maintain dose level

Maintain dose level

Decrease by 1 dose

level

Decrease by 1 dose

level

Neutropenic Fever

Omit dose until resolved, then

decrease by 2 dose levels

Decrease by 2 dose

levels

Decrease by 1 dose

level

Other

Haematological

Toxicities

Dose modifications for leucopenia, thrombocytopenia and anaemia during a cycle of

therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity

criteria and are the same as recommended for neutropenia above.

Diarrhoea

Maintain dose level

Decrease by 1 dose level

Omit dose until resolved to ≤Grade

2, then decrease by 1 dose level

Omit dose until resolved to ≤Grade

2, then decrease by 2 dose levels

Maintain dose level

Maintain dose level

Decrease by 1 dose

level

Decrease by 2 dose

levels

Maintain dose level

Maintain dose level

Decrease by 1 dose

level

Decrease by 1 dose

level

Other non-

haematological

toxicities

Maintain dose level

Decrease by 1 dose level

Omit dose until resolved to ≤Grade

2, then decrease by 1 dose level

Omit dose until resolved to ≤Grade

2, then decrease by 2 dose levels

Maintain dose level

Decrease by 1 dose

level

Decrease by 1 dose

level

Decrease by 2 dose

levels

Maintain dose level

Decrease by 1 dose

level

Decrease by 1 dose

level

Decrease by 1 dose

level

Severity of adverse events based on NCI CTC (version 2.0) see http://ctep.info.nih.gov/CTC3/default.htm.

Preparation and Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling

and preparation of infusion solutions prepared from CAMPTOSAR Injection. The use of

gloves is recommended. If a solution of CAMPTOSAR contacts the skin, wash the skin

immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous

membranes, flush thoroughly with water.

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Preparation of Infusion Solution

CAMPTOSAR Injection is intended for single use only and any unused portion should be

discarded.

CAMPTOSAR Injection must be diluted prior to infusion in 5% Glucose Injection or 0.9%

Sodium Chloride Injection to a final concentration range of 0.12 to 2.8 mg/mL. Other

drugs should not be added to the infusion solution. Parenteral drug products should be

inspected

visually

particulate

matter

discolouration

prior

administration

whenever solution and container permit.

CAMPTOSAR Injection has been shown to be chemically and physically stable when

diluted with infusion solutions (0.9% sodium chloride solution and 5% glucose solution)

for up to 28 days when stored in low-density polyethylene (LDPE) or polyvinyl chloride

(PVC) containers at 5°C or at 30°C/ambient humidity and protected from light. When

exposed to light, chemical and physical stability is indicated for up to 3 days.

It is recommended, however, that in order to reduce microbiological hazard, the infusion

solutions should be prepared immediately prior to use and infusion commenced as soon as

practicable after preparation. If not used immediately, in-use storage times and conditions

prior to use should not be longer than 24 hours at 2°C to 8°C or 6 hours at room

temperature (25°C).

Do not freeze CAMPTOSAR or admixtures of CAMPTOSAR as this may result in

precipitation of the drug.

4.3 Contraindications

CAMPTOSAR is contraindicated in patients with a known hypersensitivity to the drug or

its excipients.

CAMPTOSAR is contraindicated in women who intend to become pregnant (see section

4.6 and section 5.3).

4.4 Special warnings and precautions for use

Administration: CAMPTOSAR should be administered only under the supervision of a

physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate

management of complications is possible only when adequate diagnostic and treatment

facilities are readily available.

Extravasation: CAMPTOSAR is administered by intravenous infusion. Care should be

taken to avoid extravasation and the infusion site should be monitored for signs of

inflammation.

Should

extravasation

occur,

flushing

site

with

sterile

water

application of ice are recommended.

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“Mayo Clinic” Regimen: Except in a well-designed clinical study, CAMPTOSAR should

not be used in combination with the “Mayo Clinic” regimen of 5-FU/LV (administration for

4-5 consecutive days every 4 weeks; see Table 9) because of reports of increased toxicity,

including toxic deaths. CAMPTOSAR should be used as recommended in section 4.2.

Monitoring:

Careful

monitoring

white

blood

cell

count

with

differential,

haemoglobin, and platelet count is recommended before each dose of CAMPTOSAR.

Liver function should be monitored before initiation of treatment and monthly or as

clinically indicated.

Diarrhoea and its Management: CAMPTOSAR Injection can induce both an early and a

late form of diarrhoea that appear to be mediated by different mechanisms. Both forms of

diarrhoea may be severe.

Early diarrhoea (occurring during or shortly after infusion of CAMPTOSAR) is cholinergic

in nature. It is usually transient and only infrequently is severe. It may be accompanied by

symptoms

rhinitis,

increased

salivation,

miosis,

lacrimation,

diaphoresis,

flushing,

bradycardia

intestinal

hyperperistalsis

that

cause

abdominal

cramping.

Administration

0.25

1 mg

intravenous

subcutaneous

atropine

should

considered

(unless

clinically

contraindicated)

patients

experiencing

cholinergic

symptoms occurring during or shortly after infusion of CAMPTOSAR. Patients

65 years

of age should be closely monitored due to a greater risk of early diarrhoea observed in this

population.

Late

diarrhoea

(generally

occurring

more

than

hours

after

administration

CAMPTOSAR) can be prolonged, may lead to dehydration, electrolyte imbalance or

infection and can be life-threatening. Late diarrhoea should be treated promptly with

loperamide. Patients should be instructed to have loperamide readily available and begin

treatment at the first episode of poorly formed or loose stools or the earliest onset of bowel

movements more frequent than normally expected for the patient. One dosage regimen for

loperamide used in clinical trials consisted of 4 mg at the first onset of late diarrhoea and

then 2 mg every 2 hours until the patient was diarrhoea-free for at least 12 hours. During

the night, the patient may take 4 mg of loperamide every 4 hours. Loperamide is not

recommended to be used for more than 48 consecutive hours at these doses, because of the

risk of paralytic ileus, nor for less than 12 hours. Premedication with loperamide is not

recommended.

Patients with diarrhoea should be carefully monitored and given fluid and electrolyte

replacement if they become dehydrated and should be given antibiotics if they develop

ileus, fever or severe neutropenia. After the first treatment, subsequent chemotherapy

should be delayed until patients are diarrhoea-free (return to pre-treatment bowel function)

for at least 24 hours without the need for antidiarrhoea medication. If NCI Grade 2, 3 or 4

diarrhoea occurs, subsequent doses of CAMPTOSAR should be reduced within the current

cycle (see section 4.2).

In addition to antibiotic treatment, hospitalisation is recommended for management of the

diarrhoea,

following

cases:

diarrhoea

associated

with

fever,

severe

diarrhoea

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(requiring intravenous hydration), patients with vomiting associated with delayed (i.e. late)

diarrhoea and diarrhoea persisting beyond 48 hours following the initiation of high-dose

loperamide therapy and in the few rare instances where patients are deemed unlikely to

observe recommendations regarding management of adverse events (need for immediate

and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of delayed

diarrhoea).

Nausea and Vomiting: Irinotecan is emetogenic. It is recommended that patients receive

premedication with antiemetic agents. In clinical studies with the weekly dosage schedule,

the majority of patients received 10 mg of dexamethasone given in conjunction with

another type of antiemetic agent, such as a 5-HT

blocker (e.g., ondansetron or granisetron).

Antiemetic agents should be given on the day of treatment, starting at least 30 minutes

before

administration

CAMPTOSAR.

Physicians

should

also

consider

providing

patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

Patients with vomiting associated with delayed (i.e., late) diarrhoea should be hospitalised

as soon as possible for treatment.

Haematology: Irinotecan commonly causes neutropenia, leucopenia, and anaemia, any of

which may be severe and therefore should not be used in patients with severe bone marrow

failure (see section 4.8, Haematological). Serious thrombocytopenia is uncommon.

Neutropenia: Deaths due to sepsis following severe myelosuppression have been reported

in patients treated with CAMPTOSAR. Neutropenic complications should be managed

promptly with antibiotic support. Therapy with CAMPTOSAR should be temporarily

omitted if neutropenic fever occurs or if the absolute neutrophil count drops below 1.5 x

/L. A new cycle of therapy should not begin until the granulocyte count has recovered

to ≥1.5 x 10

/L. After the patient recovers,

subsequent doses of CAMPTOSAR should be

reduced depending upon the level of neutropenia observed (see section 4.2). Routine

administration of a colony-stimulating factor (CSF) is not necessary, but physicians may

wish to consider CSF use in individual patients experiencing significant neutropenia.

Hypersensitivity:

Hypersensitivity

reactions

including

severe

anaphylactic

anaphylactoid reactions have been observed.

Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live

or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents,

including irinotecan, may result in serious or fatal infections. Vaccination with a live

vaccine should be avoided in patients receiving irinotecan. Killed or inactivated vaccines

may be administered; however, the response to such vaccines may be diminished.

Cardiovascular: Thromboembolic events have been observed rarely in patients receiving

CAMPTOSAR. The specific cause of these events has not been determined (see section

4.8, Cardiovascular).

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Colitis/Ileus: Cases of colitis have been reported. In some cases, colitis was complicated

by ulceration, bleeding, ileus and infection. Cases of ileus without preceding colitis have

also been observed rarely. Patients experiencing ileus should receive prompt antibiotic

support.

Chronic Inflammatory Bowel Disease and/or Bowel Obstruction: Patients must not be

treated with irinotecan until resolution of the bowel obstruction.

Patients with Reduced UGT1A1 Activity: Uridine diphosphate-glucuronosyl transferase

1A1 (UGT1A1), which mediates the conjugation of the active metabolite SN-38, is encoded

by the UGT1A1 gene (see section 5.2, Biotransformation and Elimination). This gene is

highly polymorphic resulting in variable metabolic capacities among individuals. One

specific variation of the UGT1A1 gene includes a polymorphism in the promoter region

known as the UGT1A1*28 variant allele. This variant and other congenital deficiencies in

UGT1A1 expression (such as Crigler-Najjar and Gilbert’s syndrome) are associated with

reduced enzyme activity and increased systemic exposure to SN-38. Higher plasma

concentrations

SN-38

observed

individuals

homozygous

UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype) compared to patients who

have one or two wild-type alleles.

Individuals with Crigler-Najjar syndrome (types 1 and 2) or those who are homozygous for

the UGT1A1*28 allele (Gilbert’s syndrome) are at increased risk of haematological toxicity

(Grades

following

administration

irinotecan

moderate

high

doses

(>150 mg/m

). A relationship between UGT1A1 genotype and the occurrence of irinotecan

induced diarrhoea has not been established.

Patients

known

homozygous

UGT1A1*28

should

administered

normally-indicated irinotecan starting dose and monitored for haematologic toxicities. A

reduced irinotecan starting dose should be considered for patients who have experienced

haematologic toxicity with previous treatment. The exact reduction in starting dose in this

patient population has not been established and any subsequent dose modifications should

be based on individual patient tolerance to treatment.

Patients with Poor Performance Status: Physicians should exercise particular caution in

monitoring the effects of CAMPTOSAR in patients with poor performance status, in

elderly patients and in patients who have previously received pelvic/abdominal irradiation

(see section 4.8). Patients with poor performance status are at increased risk of irinotecan-

related adverse events. In patients receiving either CAMPTOSAR/5-FU/LV or 5-FU/LV in

clinical trials comparing these agents, higher rates of hospitalisation, neutropenic fever,

thromboembolism, first-cycle treatment discontinuation and early deaths were observed in

patients

with

baseline

performance

status

than

patients

with

baseline

performance of 0 or 1. Patients with performance status of 3 or 4 should not receive

CAMPTOSAR.

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Irradiation Therapy: Patients who have previously received pelvic/abdominal irradiation

increased

risk

severe

myelosuppression

following

administration

CAMPTOSAR. The concurrent administration with irradiation has not been adequately

studied and is not recommended.

Impaired Renal Function: Studies in patients with impaired renal function have not been

conducted (see section 5.2, Special Populations). Therefore, caution should be undertaken

in patients with impaired renal function. Irinotecan is not recommended for use in patients

on dialysis.

Hepatic Insufficiency: In patients with hyperbilirubinaemia, the clearance of irinotecan is

decreased and therefore the risk of haematotoxicity is increased (see section 5.2, Special

Populations).

The use of CAMPTOSAR in patients with a serum total bilirubin concentration of > 3.0 x

institutional upper limit of normal (IULN) given as a single agent on the once every 3

weeks schedule has not been established. In clinical trials of the single agent weekly dosage

schedule, patients with even modest elevations in total baseline serum total bilirubin levels

(17-34 µmol/L) had a significantly greater likelihood of experiencing first-course Grade 3

or 4 neutropenia than those with bilirubin levels that were less than 17 µmol/L (50% versus

18%; p<0.001) (see section 5.2, Special Populations and section 4.2). Patients with

deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at

greater risk of myelosuppression when receiving therapy with CAMPTOSAR.

Cholinergic Effects: CAMPTOSAR has cholinergic effects and should be used with

caution in patients with asthma or cardiovascular diseases and in patients with mechanical

intestinal or urinary obstruction.

Respiratory:

Interstitial

pulmonary

disease

presenting

pulmonary

infiltrates

uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk

factors possibly associated with the development of interstitial pulmonary disease include

pre-existing

lung

disease,

pneumotoxic

drugs,

radiation

therapy,

colony

stimulating factors. Patients with risk factors should be closely monitored for respiratory

symptoms before and during irinotecan therapy.

Others:

Since

this

product

contains

sorbitol,

unsuitable

hereditary

fructose

intolerance.

Advice

for

Patients:

Patients

should

advised

expected

toxic

effects

CAMPTOSAR, particularly of gastrointestinal complications such as nausea, vomiting,

abdominal cramping, diarrhoea and infection.

Patients should be advised to consult their physician if any of the following occur after

treatment with CAMPTOSAR: diarrhoea for the first time; inability to control diarrhoea

within 24 hours; vomiting; fever or evidence of infection; symptoms of dehydration, such

as faintness, light-headedness or dizziness; bloody or black stools; inability to take fluids by

mouth due to nausea or vomiting. Patients should also be alerted to the possibility of

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alopecia. Laxatives should be avoided (see section 4.5) and patients should contact their

physician to discuss any laxative use.

Paediatric Population: The safety and effectiveness of CAMPTOSAR in children have not

been established.

Effects on Laboratory Tests: There are no known interactions between CAMPTOSAR and

laboratory tests.

4.5 Interaction with other medicines and other forms of interaction

CYP3A4 and/or UGT1A1 Inhibitors

Irinotecan and its active metabolite SN-38 are metabolised via the human cytochrome P450

3A4 isoenzyme

(CYP3A4)

uridine

diphosphate-glucuronosyl

transferase

(UGT1A1) (see section 5.2). Coadministration of irinotecan with inhibitors of CYP3A4

and/or UGT1A1 may result in increased systemic exposure to irinotecan and the active

metabolite SN-38. Physicians should take this into consideration when administering

irinotecan with these drugs.

Ketoconazole: Irinotecan clearance is greatly reduced in patients receiving concomitant

ketoconazole, leading to increased exposure to the active metabolite SN-38. Ketoconazole

should be discontinued at least 1 week prior to starting irinotecan therapy and should not be

administered during irinotecan therapy.

Atazanavir Sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1

inhibitor, has the potential to increase systemic exposure to SN-38, the active metabolite of

irinotecan. Physicians should take this into consideration when co-administering these

drugs.

CYP3A4 Inducers

Anticonvulsants: Concomitant administration of CYP3A-inducing anticonvulsant drugs

(e.g., carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to SN-38.

Consideration

should

given

starting

substituting

non-enzyme-inducing

anticonvulsants at least one week prior to initiation of irinotecan therapy in patients

requiring anticonvulsant treatment.

St. John’s Wort (Hypericum perforatum): Exposure to the active metabolite SN-38 is

reduced in patients taking concomitant St. John’s Wort. St. John’s Wort should be

discontinued at least 1 week prior to the first cycle of irinotecan, and should not be

administered during irinotecan therapy.

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Other Interactions

Neuromuscular

Blocking

Agents:

Interaction

between

irinotecan

neuromuscular

blocking agents cannot be ruled out. Since irinotecan has anticholinesterase activity, drugs

with

anticholinesterase

activity

prolong

neuromuscular

blocking

effects

suxamethonium

neuromuscular

blockade

non-depolarising

drugs

antagonised.

Antineoplastic Agents: The adverse effects of CAMPTOSAR, such as myelosuppression

and diarrhoea, would be expected to be exacerbated by other antineoplastic agents having

similar adverse effects.

Dexamethasone: Lymphocytopenia has been reported in patients receiving CAMPTOSAR

and it is possible that the administration of dexamethasone as antiemetic prophylaxis may

have enhanced the likelihood of this effect. However, serious opportunistic infections have

been

observed

complications

have

specifically

been

attributed

lymphocytopenia.

Hyperglycaemia has also been reported in patients receiving CAMPTOSAR. Usually this

has been observed in patients with a history of diabetes mellitus or evidence of glucose

intolerance prior to administration of CAMPTOSAR. It is probable that dexamethasone,

given as antiemetic prophylaxis, contributed to hyperglycaemia in some patients.

Prochlorperazine: The incidence of akathisia in clinical trials of the single agent weekly

dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered

on the same day as CAMPTOSAR than when these drugs were given on separate days

(1.3%, 1/80 patients). However, the 8.5% incidence of akathisia is within the range

reported

prochlorperazine

when

given

premedication

other

chemotherapies.

Laxatives: It would be expected that the incidence or severity of diarrhoea would be

worsened by laxative use during therapy with CAMPTOSAR, but this has not been studied.

Diuretics: In view of the potential risk of dehydration secondary to vomiting and/or

diarrhoea induced by CAMPTOSAR, the physician may wish to withhold diuretics during

dosing with CAMPTOSAR and, certainly, during periods of active vomiting or diarrhoea.

4.6 Fertility, pregnancy and lactation

Fertility

No significant adverse effects on fertility and general reproductive performance were

observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to

rats. Atrophy of male reproductive organs was observed after multiple daily irinotecan

doses both in rodents at 20 mg/kg (AUC approximately the same value as in patients

administered 125 mg/m

weekly) and dogs at 0.4 mg/kg (AUC about 1/15

the value in

patients administered 125 mg/m

weekly).

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Pregnancy- Category D.

CAMPTOSAR

cause

fetal

harm

when

administered

pregnant

woman.

Administration of 6 mg/kg/day intravenous irinotecan hydrochloride to rats (AUC about 0.2

times the corresponding values in patients administered 125 mg/m

) and rabbits (about one-

half the recommended human weekly starting dose on a mg/m

basis) during the period of

organogenesis, is embryotoxic as characterised by increased post-implantation loss and

decreased numbers of live fetuses. Irinotecan hydrochloride was teratogenic in rats at doses

greater

than

1.2 mg/kg/day

(AUC

about

1/40

corresponding

values

patients

administered 125 mg/m

) and in rabbits at 6.0 mg/kg/day. Teratogenic effects included a

variety of external, visceral, and skeletal abnormalities.

There are no adequate and well-controlled studies of irinotecan hydrochloride in pregnant

women. If the drug is used during pregnancy, or if the patient becomes pregnant while

receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant while

receiving treatment with CAMPTOSAR.

Lactation

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of

radiolabelled irinotecan hydrochloride and was concentrated up to 65-fold at 4 hours after

administration relative to plasma concentrations. As many drugs are excreted in human

milk and because of the potential for serious adverse reactions in nursing infants, it is

recommended that nursing be discontinued when receiving therapy with CAMPTOSAR.

4.7 Effects on ability to drive and use machinery

The effect of irinotecan on the ability to drive or use machinery has not been evaluated.

However, patients should be warned about the potential for dizziness or visual disturbances

which may occur within 24 hours following the administration of irinotecan, and advised

not to drive or operate machinery if these symptoms occur.

4.8 Undesirable effects

Combination Therapy

In the two Phase III studies, a total of 955 patients with metastatic colorectal cancer

received

irinotecan

hydrochloride

combination

with

5-FU/LV,

5-FU/LV

alone,

irinotecan hydrochloride alone (see section 5.1, Clinical Efficacy and Safety, Table 9). In

these studies, 370 patients received irinotecan in combination with 5-FU/LV, 362 patients

received 5-FU/LV alone, and 223 patients received irinotecan hydrochloride alone.

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Fifty-nine (6.1%) patients died within 30 days of study treatment: 27 (7.3%) received

irinotecan hydrochloride in combination with 5-FU/LV, 19 (5.3%) received 5-FU/LV alone,

and 13 (5.8%) received irinotecan hydrochloride alone. Deaths potentially related to

treatment

occurred

(0.7%)

patients

received

irinotecan

hydrochloride

combination with 5-FU/LV (2 neutropenic fever/sepsis, 1 treatment toxicity), 3 (0.7%)

patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during

thrombocytopenia,

unknown)

(0.9%)

patients

received

irinotecan

hydrochloride alone (2 neutropenic fever). Deaths within 60 days of study treatment were

reported for 18 (4.9%) patients who received irinotecan hydrochloride in combination with

5-FU/LV, 18 (5.0%) patients who received 5-FU/LV alone and 15 (6.7%) patients who

received irinotecan hydrochloride alone. Discontinuations due to adverse events were

reported for 26 (7.0%) patients who received irinotecan hydrochloride in combination with

5-FU/LV, 15 (4.1%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who

received irinotecan hydrochloride alone.

Table

lists

Grade

clinically

relevant

adverse

events

reported

combination treatment arms of the two Phase III studies.

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Table 6: Percent (%) of Patients Experiencing Clinically Relevant Grade 3 and 4

Adverse Events in Phase III Studies of Combination Therapies

a

Study 1

Study 2

Adverse Event

Irinotecan HCl

5-FU/LV

n=225

5-FU/LV

n=219

Irinotecan

n=223

Irinotecan HCl

5-FU/LV

n=145

5-FU/LV

N=143

Total Grade 3/4 Adverse Events

53.3

45.7

45.7

72.4

39.2

GASTROINTESTINAL

Diarrhoea - late

- Grade 3

- Grade 4

Diarrhoea - early

Nausea

Abdominal pain

Vomiting

Anorexia

Constipation

Mucositis

22.7

15.1

15. 6

14.6

13.2

11.5

16.9

31.0

18.4

12.6

16.1

13.0

12.1

14.5

10.3

HAEMATOLOGICAL

Neutropenia

- Grade 3

- Grade 4

Leucopenia

Anaemia

Neutropenic fever

Thrombocytopenia

Neutropenic infection

53.8

29.8

24.0

37.8

66.7

23.7

42.5

23.3

14.6

31.0

19.3

12.1

21.5

46.2

36.4

17.4

13.4

12.7

BODY AS A WHOLE

Asthenia

Pain

Fever

Infection

19.5

11.9

13.9

METABOLIC &

NUTRITIONAL

Increased bilirubin

10.6

DERMATOLOGICAL

Exfoliative dermatitis

Rash

Hand and foot syndrome

Cutaneous signs

RESPIRATORY

Dyspnoea

Cough

Pneumonia

NEUROLOGICAL

Dizziness

Somnolence

Confusion

CARDIOVASCULAR

Vasodilation

Hypotension

Thrombophlebitis

Pulmonary embolus

Myocardial infarction

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Severity of adverse events based on NCI CTC (version 1.0), see http://ctep.info.nih.gov/CTC3/default.htm.

Number of patients in the as-treated population for each group.

Number of patients treated in the de Gramont regimen (B2/C2 treatment arms of Table 9).

most

clinically

significant

adverse

events

patients

receiving

irinotecan

hydrochloride-based therapy were diarrhoea, nausea, vomiting, neutropenia and alopecia.

The most clinically significant adverse events for patients receiving 5-FU/LV therapy were

diarrhoea, neutropenia, neutropenic fever and mucositis. In Study 1, Grade 4 neutropenia,

neutropenic fever (defined as ≥Grade 2 fever and Grade 4 neutropenia), and mucositis were

observed less often with irinotecan hydrochloride/5-FU/LV than with administration of

5-FU/LV.

Single Agent Therapy

Information on adverse reactions for CAMPTOSAR as single agent therapy is available

from 304 patients with metastatic carcinoma of the colon or rectum treated in Phase II trials

with the once weekly dosage schedule, 316 patients treated with the once-every-3-week

dosage schedule and over 1100 patients with a variety of tumour types treated in Japan. In

general the types of toxicities observed were similar. 4.3% of patients treated with the

weekly dosage schedule and 8% of patients treated with the once-every-3-week dosage

schedule discontinued treatment with CAMPTOSAR because of medical events.

Seventeen of the 304 patients treated with the weekly dosage schedule died within 30 days

administration

CAMPTOSAR

five

cases

(1.6%),

deaths

were

potentially drug-related. Eleven patients treated with irinotecan hydrochloride in the once-

every-3-week dosage schedule died within 30 days of treatment and in three cases (1%), the

deaths were potentially related to treatment with irinotecan hydrochloride. The main causes

of the deaths potentially related to treatment were neutropenic infection, Grade 4 diarrhoea

and asthenia.

The frequency of the most common adverse events reported from the single agent second

line studies is presented in Table 7 below. Additional information on adverse events

follows the table, organised by body system category.

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Table 7: Adverse events reported from the second line single agent therapy in

304 patients

a

Weekly dosage schedule

3 weekly dosage schedule

(NCI Grade 3 & 4 only)

Event

% of

Patients

%NCI Grade 3

& 4

Study 1 (%)

Study 2 (%)

GASTROINTESTINAL

Diarrhoea (late)

Nausea

Vomiting

Abdominal

cramping/pain

Anorexia

Diarrhoea (early)

Constipation

Flatulence

Stomatitis

Dyspepsia

87.8

86.2

66.8

56.9

54.9

50.7

29.9

12.2

11.8

10.5

30.6

16.8

12.5

16.4

21.7

13.8

13.8

13.8

12.2

22.0

11.0

14.2

HAEMATOLOGICAL

Leucopenia

Anaemia

Neutropenia

Thrombocytopenia

63.2

60.5

53.9

28.0

26.3

22.2

22.2

14.2

14.2

BODY AS A WHOLE

Asthenia

Fever

Pain

Headache

Back pain

Chills

Minor infection

Oedema

Abdominal enlargement

75.7

45.4

23.7

16.8

14.5

13.8

14.5

10.2

10.2

12.2

14.8

18.5

13.4

16.5

METABOLIC AND NUTRITIONAL

Weight reduction

Dehydration

Increased alkaline phosphatase

Increased SGOT

30.3

14.8

13.2

10.5

DERMATOLOGICAL

Alopecia

Sweating

Rash

60.5

16.4

12.8

RESPIRATORY

Dyspnoea

Increased coughing

Rhinitis

22.0

17.4

15.5

Severity of adverse events based on NCI CTC (version 1.0), see http://ctep.info.nih.gov/CTC3/default.htm.

Combined results for leucopenia/neutropenia are presented for the once-every-3-week dosage schedule.

In this study, 22.2% of patients treated with best supportive care experienced NCI Grade 3/4 pain.

In this study, 13.2% of patients treated with infusional 5-FU experienced NCI Grade 3/4 pain.

Complete hair loss = NCI Grade 2.

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Overview of Adverse Events

Gastrointestinal: Nausea, vomiting, and diarrhoea are common adverse events following

treatment with CAMPTOSAR and can be severe. Among those patients treated at the

125 mg/m

single agent weekly dose, the median duration of any grade of late diarrhoea

was 3 days and for Grade 3 or 4 late diarrhoea was 7 days. The frequency of Grade 3 or 4

late diarrhoea was significantly greater in patients 65 years or older (39.8% versus 23.4%,

p=0.0025).

Abdominal pain and cramping are associated with early-onset diarrhoea (diarrhoea which

occurs within 24 hours of drug administration). In studies it has been found that atropine is

useful in ameliorating these events. Colonic ulceration, sometimes with gastrointestinal

bleeding, ileus and infection, has been observed in association with administration of

CAMPTOSAR.

Haematological:

CAMPTOSAR

commonly

causes

neutropenia,

leucopenia

(including

lymphocytopenia), and anaemia. Serious thrombocytopenia is uncommon. In clinical

studies with the single agent weekly dosage schedule, one death due to neutropenic sepsis

without fever was judged to be potentially drug-related (0.3%, 1/304). Blood transfusions

were given to 9.9% of patients. When evaluated in the trials of single agent weekly

administration, the frequency of Grade 3 and 4 neutropenia was significantly higher in

patients who received previous pelvic/abdominal irradiation than in those who had not

received such irradiation (48.1% versus 24.1%, p=0.0356). In these same studies, patients

with total baseline serum bilirubin levels of 17 µmol/L or more also had a significantly

greater likelihood of experiencing first-course Grade 3 or 4 neutropenia than those with

bilirubin levels that were less than 17 µmol/L (50% versus 17.7%, p<0.001).

Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis, increased

salivation, miosis, lacrimation, diaphoresis, flushing and intestinal hyperperistalsis that can

cause abdominal cramping and early diarrhoea. If these symptoms occur, they manifest

during

shortly

after

drug

infusion.

They

thought

related

anticholinesterase activity of the irinotecan parent compound and are more likely to occur at

higher doses. The timing of the symptoms is most consistent with the occurrence of peak

irinotecan hydrochloride serum levels during parenteral administration.

Metabolic and Nutritional: The dehydration observed in 14.8% of patients in clinical

studies was as a consequence of diarrhoea, nausea and vomiting.

Hepatic: In the clinical studies evaluating the single agent weekly dosage schedule, NCI

Grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients.

These events typically occur in patients with known hepatic metastases. For the once-

every-3-week dosage schedule, hepatic events, such as ascites and jaundice of NCI Grade

3/4 severity, occurred in 8.5% of patients in one study and 8.7% of patients in another

study.

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Renal: Increases in serum creatinine or blood urea nitrogen, generally attributable to

complications of infection or to dehydration related to nausea, vomiting or diarrhoea have

been observed. There have been cases of acute renal failure. Rare instances of renal

dysfunction due to tumour lysis syndrome have also been reported.

Dermatological: Alopecia has been reported during treatment with CAMPTOSAR. Rashes

have also been reported but did not result in discontinuation of treatment.

Respiratory: Severe pulmonary events are infrequent. Over half the patients with dyspnoea

clinical

studies

evaluating

single agent weekly dosage schedule had lung

metastases; the extent to which malignant pulmonary involvement or other pre-existing

lung disease may have contributed to dyspnoea in these patients is unknown. For the once-

every-3-week dosage schedule, respiratory events, such as dyspnoea and cough of NCI

Grade 3/4 severity occurred in 10.1% of patients in one study and 4.7% of patients in

another study.

A potentially life-threatening pulmonary syndrome, consisting of dyspnoea, fever and a

reticulonodular pattern on chest x-ray was observed in a small percentage of patients in

early Japanese studies. The contribution of irinotecan hydrochloride to these preliminary

events was difficult to assess because these patients also had lung tumours and some had

pre-existing nonmalignant pulmonary disease. As a result of these observations, however,

clinical studies in the USA enrolled few patients with compromised pulmonary function,

significant ascites, or pleural effusions.

Neurological: Insomnia and dizziness were observed in 19.4% and 14.8% respectively of

patients studied in clinical trials of the single agent weekly dosage schedule, but were not

usually considered to be directly related to the administration of CAMPTOSAR. Dizziness

may sometimes represent symptomatic evidence of orthostatic hypotension in patients with

dehydration.

Cardiovascular:

Vasodilation

(flushing)

occur

during

administration

CAMPTOSAR. Irinotecan hydrochloride has anti-cholinesterase activity. As such, there

are possible cardiovascular effects due to its administration. These include sudden death,

blackout and bradycardia. Patients should be monitored for cholinergic effects during

administration of CAMPTOSAR and atropine should be readily available for treatment of

these effects. There were no cases of sudden death reported in the Phase II clinical studies

of the single agent weekly dosage schedule involving 304 patients. In these studies, two

patients (0.7%) suffered syncope and one patient (0.3%) suffered bradycardia.

Thromboembolic events including angina pectoris, arterial thrombosis, cerebral infarct,

cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest,

myocardial infarct, myocardial ischaemia, peripheral vascular disorder, pulmonary embolus,

sudden death, thrombophlebitis, thrombosis and vascular disorder have been observed

rarely in patients receiving CAMPTOSAR. The specific cause of these events has not been

determined.

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Other: Other NCI Grade 3 or 4 drug-related adverse events observed in 1-10% of patients

in clinical trials included mucositis, bilirubinaemia and hypovolaemia. In fewer than 1% of

patients,

Grade

rectal

disorder,

gastrointestinal

monilia,

hypokalaemia,

hypomagnesaemia, increased GGTP, malaise, sepsis and abnormal gait were observed.

Post-marketing Surveillance

Cardiac Disorders: Myocardial ischaemic events have been observed following irinotecan

therapy predominantly in patients with underlying cardiac disease, other known risk factors

for cardiac disease or previous cytotoxic chemotherapy.

Gastrointestinal Disorders: Infrequent cases of intestinal obstruction, ileus, megacolon or

gastrointestinal

haemorrhage,

rare

cases

colitis,

including

typhlitis

(ileocaecal

syndrome), ischaemic and ulcerative colitis have been reported. In some cases, colitis was

complicated by ulceration, bleeding, ileus or infection. Cases of ileus without preceding

colitis have also been reported. Rare cases of intestinal perforation have been reported.

Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have

been observed.

Hypovolaemia: There have been rare cases of renal impairment and acute renal failure,

generally

patients

became

infected

and/or

volume

depleted

from

severe

gastrointestinal

toxicities.

Infrequent

cases

renal

insufficiency,

hypotension

circulatory failure have been observed in patients who experienced episodes of dehydration

associated with diarrhoea and/or vomiting, or sepsis.

Infections and Infestations: Bacterial, fungal and viral infections have been reported.

Immune System Disorders: Hypersensitivity reactions including severe anaphylactic or

anaphylactoid reactions have been reported.

Investigations: Rare cases of hyponatraemia mostly related with diarrhoea and vomiting

have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the

absence of progressive liver metastasis, transient increase of amylase and occasionally

transient increase of lipase have been very rarely reported.

Musculoskeletal

and

Connective

Tissue

Disorders:

Early

effects

such

muscular

contraction or cramps and paresthaesia have been reported.

Nervous System Disorders: Speech disorders, generally transient in nature, have been

reported in patients treated with irinotecan; in some cases, the event was attributed to the

cholinergic syndrome observed during or shortly after infusion of irinotecan.

Respiratory, Thoracic and Mediastinal Disorders: Interstitial pulmonary disease presenting

as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as

dyspnoea have been reported (see section 4.4). Hiccups have also been reported.

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Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals

asked

report

suspected

adverse

reactions.

https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

In humans, at single doses up to 750 mg/m

, adverse events were similar to those reported

with the recommended dosage regimens. There have been reports of overdosage at doses

up to approximately twice the recommended therapeutic dose, which may be fatal. The

most significant adverse reactions reported were severe neutropenia and severe diarrhoea.

There is no known antidote for overdosage of CAMPTOSAR. Support respiratory and

cardiovascular

function.

Maximum

supportive

care

should

instituted

prevent

dehydration due to diarrhoea and to treat any infectious complications.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5. PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Mechanism of Action

CAMPTOSAR Injection (irinotecan hydrochloride injection) is an antineoplastic agent of

the topoisomerase I inhibitor class.

Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract

from plants such as Camptotheca acuminata. Irinotecan hydrochloride is a pale yellow to

yellow crystalline powder that is slightly soluble in water and organic solvents.

Pharmacodynamic Effects

Irinotecan

hydrochloride

derivative

camptothecin.

Camptothecins

interact

specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by

inducing reversible single-strand breaks. Irinotecan hydrochloride and its active metabolite

SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-

strand breaks. Current research suggests that the cytotoxicity of irinotecan hydrochloride is

due to double-strand DNA damage produced during DNA synthesis when replication

enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either

irinotecan hydrochloride or SN-38. Mammalian cells cannot efficiently repair these double-

strand breaks.

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Irinotecan hydrochloride serves as a water-soluble precursor of the lipophilic metabolite

SN-38, which is approximately 1000 times as potent as irinotecan hydrochloride as an

inhibitor of topoisomerase I purified from human and rodent tumour cell lines. However,

the precise contribution of SN-38 to the activity of CAMPTOSAR is unknown. Both

irinotecan hydrochloride and SN-38 exist in an active lactone form and an inactive hydroxy

acid anion form. An acidic pH promotes the formation of the lactone whereas a basic pH

favours the hydroxy acid anion form.

Administration of irinotecan hydrochloride has resulted in antitumour activity in mice

bearing cancers of rodent origin and in human carcinoma xenografts of various histological

types.

Irinotecan

hydrochloride

non-competitive

inhibitor

acetylcholinesterase

cholinergic syndrome is associated with its administration (see section 4.8).

Clinical Efficacy and Safety

CAMPTOSAR has been studied in clinical trials in combination with 5-FU and LV as a

first-line agent in metastatic colorectal cancer and as a single agent used after failure of

initial therapy. Weekly and once every 3 weeks dosage schedules were studied using

CAMPTOSAR as the single agent. Weekly and once every 2 week schedules were studied

with CAMPTOSAR used in combination treatment. Patients with a WHO performance

status of 3 or 4 have not been studied in clinical trials (see Table 8).

Table 8: WHO scale for performance status

Fully active; able to carry on all pre-disease performance without restriction

Restricted in physically strenuous activity but ambulatory and able to carry out work of a

light or sedentary nature

Ambulatory and capable of self-care but unable to carry out any work activities; up and

about more than 50% of waking hours

Capable of only limited self-care; confined to bed or chair more than 50% of waking hours

Completely disabled; cannot carry out any self-care; totally confined to bed or chair

Combination therapy for first-line treatment of metastatic colorectal cancer

Two randomised, open-label, controlled, multinational, Phase III clinical trials support the

use of CAMPTOSAR as first-line treatment of patients with metastatic carcinoma of the

colon or rectum. The dosing regimens of these studies are given in Table 9.

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Table 9: Dosage regimen of the studies evaluating the first line treatment of metastatic

colorectal cancer

Arm

Agent

Study 1 Dosing Regimen

Study 2 Dosing Regimen

Irinotecan HCl

125 mg/m

irinotecan HCl IV infusion

over 90 mins.

Treatment was administered once

weekly for four weeks with treatment

resuming on Day 43.

Irinotecan HCl

5-FU

125 mg/m

irinotecan HCl IV infusion

over 90 mins followed immediately by

20 mg/m

LV administered as an IV

bolus injection and then 500 mg/m

5-FU as an IV bolus injection.

Treatment was administered once

weekly for four weeks with treatment

resuming on Day 43 (Saltz regimen)

80 mg/m

IV infusion over 90 mins of

irinotecan HCl plus a 500 mg/m

IV infusion over 2 hours followed

immediately by an 2300 mg/m

5-FU

IV infusion over 24 hours.

Treatment was administered once

weekly for six weeks with treatment

resuming on Day 50 (AIO regimen)

Irinotecan HCl

5-FU

180 mg/m

IV infusion over 90 mins

of irinotecan HCl on Day 1, plus one

hour later a 200mg/m

LV IV infusion

over 2 hours followed immediately by

a 400 mg/m

5-FU IV bolus injection

and a 600 mg/m

5-FU IV infusion

over 22 hours on Days 1 and 2.

Treatment was administered every

2 weeks (de Gramont regimen)

5-FU

20 mg/m

LV administered as an IV

bolus injection followed immediately

by 425 mg/m

5-FU as an IV bolus

injection.

Treatment was given for 5 consecutive

days with the treatment repeating on

Day 29 (Mayo Clinic regimen)

500 mg/m

LV IV infusion over

2 hours followed immediately by a

2600 mg/m

5-FU IV infusion over

24 hours.

Administration was weekly for

6 weeks with treatment resuming on

Day 50 (AIO regimen)

5-FU

200 mg/m

LV IV infusion over

2 hours followed immediately by a

400 mg/m

5-FU IV bolus injection

and a 600 mg/m

5-FU IV infusion

over 22 hours on Days 1 and 2.

Treatment was administered every

2 weeks (de Gramont regimen)

Based on the Saltz, Mayo Clinic, de Gramont and Association of Medical Oncology of the German Cancer

Society (AIO) dosing regimens.

In both studies, concomitant medications such as antiemetics, atropine and loperamide were

given to patients for prophylaxis and /or management of symptoms from treatment. In

study 2, if late diarrhoea persisted for greater than 24 hours despite loperamide, a 7 day

course

fluoroquinolone

antibiotic

prophylaxis

given.

Treatment

with

oral

fluoroquinolone

initiated

patients

whose

diarrhoea

persisted

greater

than

24 hours

despite

loperamide

they

developed

fever

addition

diarrhoea.

Treatment with oral fluoroquinolone was also initiated in patients who developed an

absolute neutrophil count (ANC) <0.5 x 10

/L, even in the absence of fever or diarrhoea.

Patients also received treatment with intravenous antibiotics if they had persistent diarrhoea

or fever or if ileus developed.

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In both studies the combination of irinotecan hydrochloride/5-FU/LV therapy resulted in

significant improvement in objective tumour response rate, time to tumour progression

(TTP), and survival when compared with 5-FU/LV alone. These differences in survival

were observed despite the use of post-study second-line therapy, including irinotecan-

containing regimens in patients in the control arm. Patient characteristics and major

efficacy results are shown in Table 10.

Table 10: Combination therapy in first line treatment of metastatic colorectal cancer:

Study Results

Study 1

Study 2

Irinotecan

+

bolus 5-

FU/LV

Bolus 5-

FU/LV

Irinotecan

Irinotecan

+

Infusional

5 FU/LV

Infusional

5-FU/LV

Number of patients

Demographics and Treatment Administration

Female/Male (%)

34/65

45/54

35/64

33/67

47/53

Median Age in years (range)

62 (25-85)

61 (19-85)

61 (30-87)

62 (27-75)

59 (24-75)

Performance Status (%)

Median Primary Tumour (%)

Colon

Rectum

Median Time from Diagnosis to

Randomisation (months, range)

(0-161)

(0-203)

(0.1-185)

(0-88)

(0-104)

Prior Adjuvant 5-FU Therapy (%)

Median Duration of Study

Treatment (months)

Median Relative Dose Intensity (%)

Irinotecan

5-FU

Efficacy Results

Confirmed Objective Tumour

Response Rate

(%) [95% CI]

[33-46]

[16-27]

[13-24]

[28-42]

[16-29]

Median Time to Tumour Progression

(months) [95% CI]

[5.4-8.0]

[3.7-4.6]

[3.9-5.0]

[5.7-8.0]

[3.2-5.5]

Median Survival (months) [95% CI]

14.8

[12.3-17.1]

12.6

[11.1-14.6]

12.0

[11.3-13.5]

17.4

[15.2-20.2]

14.1

[12.6-17.4]

See Table 8.

Confirmed ≥4 to 6 weeks after first evidence of objective response.

Improvement

noted

when

response

rates

time

tumour

progression

were

examined across all demographic and disease-related sub-groups (as categorised by age,

gender, ethnic origin, performance status, extent of organ involvement with cancer, time

from diagnosis of cancer, prior adjuvant therapy and baseline laboratory abnormalities),

with irinotecan hydrochloride-based combination therapy relative to 5-FU/LV.

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European

Organisation

Research

Treatment

Cancer

Quality

Life

Questionnaire (EORTC QLQ-C30) was used in both studies. While there was no statistical

evidence that there were significant differences between irinotecan hydrochloride/5-FU/LV

combination and 5-FU/LV alone with regard to Quality of Life (QOL) improvement,

descriptive evidence suggested a general trend favouring QOL improvement or less-

worsening in favour of the irinotecan hydrochloride combination regimen.

Single Agent Treatment in Recurrent or Progressive Metastatic Colorectal Cancer

After 5-FU Based Treatment

Weekly Dosage Schedule

Three multicentre, open-label, Phase II studies, all utilising repeated courses of once weekly

treatment with CAMPTOSAR for 4 consecutive weeks, followed by a two week rest period

were conducted in a total of 304 patients in the United States. These studies were designed

evaluate

tumour

response

rate

toxicity

with

CAMPTOSAR

patients

with

metastatic colorectal cancer that recurred or progressed following a prior 5-FU based

chemotherapeutic regimen. Starting doses of CAMPTOSAR in these trials were 100, 125

or 150 mg/m

with 150 mg/m

proving to be poorly tolerated due to unacceptably high rates

of Grade 4 late diarrhoea and febrile neutropaenia. The results of the individual studies are

shown in Table 11.

Table 11: Phase II clinical studies with the once weekly dosage schedule

Study

Number of Patients

Dose (mg/m

/wk x 4)

Prior 5-FU therapy (%)

For metastatic disease

81.3

65.5

73.4

67.7

6 months after adjuvant

14.6

26.6

27.5

>6 months after adjuvant

15.6

Classification unknown

12.2

Duration of treatment (median, months)

Median relative dose intensity (%)

Objective response rate (%)

[95% CI]

20.8

[9.3-32.3]

13.3

[6.3-20.4]

14.1

[5.5-22.6]

[3.3-14.3]

Time to response (median, months)

Response duration (median, months)

Survival (median, months)

10.4

10.7

The initial dose in Study C was 125 mg/m

but was reduced to 100 mg/m

because the toxicity at the starting

dose was perceived to be greater than seen in previous studies. Results are analysed separately for the two

starting doses.

Nine patients received 150 mg/m

as a starting dose; 2 (22.2%) responded to CAMPTOSAR.

Relative dose intensity for CAMPTOSAR based on planned dose intensity of 100, 83.3 and 66.7 mg/m

corresponding with 150, 125 and 100 mg/m

starting doses respectively.

There were 2 complete responses and 38 partial responses.

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Of the 304 patients treated in the Phase II studies, response rates to CAMPTOSAR were

similar in males and females and among patients younger than 65 years. Rates were also

similar in patients with cancer of the colon or cancer of the rectum and in patients with

single and multiple metastatic sites. Response rate was 18.5% in patients with a WHO

performance status of 0 and 8.2% in patients with a performance status of 1 or 2.

The response rates with CAMPTOSAR were unaffected by whether or not patients had

responded to prior 5-FU based treatment given for metastatic disease. Patients who had

received previous irradiation to the pelvis responded to CAMPTOSAR at approximately the

same rate as those who had not previously received irradiation.

Overall, across the pivotal studies, stable disease was documented in 148 (48.7%) of the

304 patients in the intent to treat population and in 145 (55.6%) of the 261 patients in the

evaluable

population.

Consistent

with

results

Study

somewhat

greater

percentage of patients who were treated with the 125 mg/m

starting dose (53.4%; 103/193)

than with the 100 mg/m

starting dose (39.2%; 40/102) had stable disease during therapy.

Once Every 3 Week Dosage Schedule

Two Phase III, multicentre, randomised studies were conducted with a three weekly dosage

regimen

patients

with

metastatic

colorectal cancer whose disease had recurred or

progressed following 5-FU therapy (n=535). Second-line irinotecan hydrochloride was

compared with best supportive care in one study and with infusional 5-FU-based therapy in

the second study. The primary endpoint in both studies was survival. Parameters of

clinical benefit and quality of life were also assessed. The starting dose was 350 mg/m

infused intravenously over 90 minutes to a maximum total dose of 700 mg. For patients

70 years or older and for patients with a WHO performance status of 2 the starting dose was

reduced to 300 mg/m

. Antiemetics, atropine and loperamide were provided as supportive

care and late diarrhoea persisting for greater than 24 hours despite loperamide was treated

with a 7-day course of a fluoroquinolone antibiotic.

A significant survival advantage for irinotecan hydrochloride over best supportive care or

infusional 5-FU-based therapy was demonstrated. When adjusted for baseline patient

characteristics (e.g., performance status), survival among patients treated with irinotecan

hydrochloride remained significantly longer than in the control populations (p=0.001 for

Study 1 and p=0.017 for Study 2). Clinical benefit in Study 1, as measured by pain-free

survival and survival without weight loss, was significantly longer for patients treated with

irinotecan hydrochloride than for patients in the best supportive care group (p=0.01 and

p=0.05 respectively). The results are summarised in Table 12.

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Table 12. Phase III clinical studies with a Once-Every-3-Week Dosage Schedule:

Study 1

Study 2

Irinotecan

hydrochloride

Best Supportive

Care

Irinotecan

hydrochloride

5-FU

Number of Patients

Prior 5-FU therapy (%)

For metastatic disease

≤3/6 months after adjuvant

>3/6 months after adjuvant

Duration of treatment (mean, months)

[95%CI]

[4.2-5.0]

[3.8-5.0]

[3.3-4.1]

Median relative dose intensity (%)

81-99

Survival (median, months) [95% CI]

[8.4-10.7]

[5.0-7.6]

10.8

[9.5-12.8]

[7.7-10.5]

1-year survival (%) [95% CI]

36.2

[29.3-43.1]

13.8

[6.7-20.9]

44.8

[36.2-53.4]

32.4

[24.3-40.5]

Progression-free survival (median,

months) [95% CI]

[3.8-4.8]

[2.6-3.7]

Symptom-free survival (median,

months) [95% CI]

[3.8-7.6]

[2.2-6.9]

[6.1-10.7]

[4.4-8.7]

Pain-free survival (median, months)

[95% CI]

[5.8-8.4]

[1.8-5.1]

10.3

[7.8-**]

[6.2-10.2]

Median survival without performance

status deterioration (%) [95% CI]

[4.3-6.6]

[1.9-3.7]

[5.2-7.6]

[4.2-6.2]

Time to weight loss ≥5% (median,

months) [95% CI]

[5.5-7.6]

[3.4-5.1]

[6.7-12.3]

[4.7-11.6]

One of the following 5-FU regimens was used:

Leucovorin 200 mg/m

iv over 2 hours; followed by 5-FU 400 mg/m

iv bolus; followed by 5-FU

600 mg/m

continuous iv infusion over 22 hours on Days 1 and 2 every 2 weeks.

(ii)

5-FU 250-300 mg/m

/day protracted continuous iv infusion until toxicity.

(iii)

5-FU 2.6-3 g/m

/day iv over 24 hours every week for 6 weeks with or without leucovorin

20-500 mg/m

/day every week iv for 6 weeks with a 2 week rest between cycles.

Study 1 ≤6 months; Study 2

≤3 months.

Relative dose intensity for irinotecan HCl based on planned dose intensity of 116.7 mg/m

/week. Dose

intensity in patients receiving 5-FU in Study 2 varied depending upon the type of regimen.

** Cannot be estimated due to small sample size.

In the two Phase III studies, quality of life was assessed using the European Organisation on

Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). In

Study 1, the global quality of life scores were significantly higher for patients treated with

irinotecan hydrochloride than for those who received best supportive care (p=0.0013). In

Study 2, the global quality of life scores were similar for patients who received either

irinotecan hydrochloride or infusional 5-FU.

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Other Studies

A Japanese open-label, uncontrolled, late Phase II study in patients with non-small-cell lung

cancer enrolled a total of 153 patients. In this study, pneumonitis occurred in 6.2% (9/146)

of the patients. One patient died of interstitial pneumonitis. CAMPTOSAR was given at a

dose of 100 mg/m

intravenously once weekly. Dosage adjustments were made according

to toxicity and the duration of treatment was until disease progression or unacceptable

toxicity occurred (with each patient to receive at least three doses).

5.2 Pharmacokinetic properties

Absorption and Distribution

After intravenous infusion of irinotecan hydrochloride in humans with various cancers,

irinotecan hydrochloride plasma concentrations decline in a multiexponential manner, with

mean

terminal

elimination

half-life

about

hours.

mean

terminal

elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. In a study

where irinotecan hydrochloride was administered at doses of 100-750 mg/m

by 30 minute

intravenous infusion every three weeks, the plasma terminal elimination half-life was 14.2

+/- 7.7 hours for irinotecan hydrochloride and 13.8 +/- 1.4 hours for SN-38.

Over

recommended

dose

range

350 mg/m

irinotecan

hydrochloride

increases

linearly

with

dose;

SN-38

increases

less

than

proportionally with dose. Maximum concentrations of the active metabolite SN-38 are

generally seen within 1 hour following the end of a 90-minute infusion of irinotecan

hydrochloride.

Pharmacokinetic parameters for irinotecan and SN-38 following a 90 minute infusion of

irinotecan hydrochloride at dose levels of 125 and 340 mg/m

determined in two clinical

studies in patients with solid tumours are summarised in Table 13.

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Table 13: Summary of Mean (± Standard Deviation) Irinotecan Hydrochloride and

SN-38 Pharmacokinetic Parameters in Patients with Solid Tumours

Dose

(mg/m

Irinotecan

SN-38

(ng/mL)

0-24

(ng.hr/mL)

(hr)

area

(L/m

(L/hr/m

(ng/mL)

0-24

(ng.hr/mL)

(hr)

(N = 64)

1,660 ±

10,200 ±

3270

110 ±

48.5

13.3 ±

6.01

26.3 ±

11.9

229 ± 108

10.4

(N = 6)

3,392 ±

20,604 ±

6,027

11.7

234 ±

69.6

13.9 ±

4.00

56.0 ±

28.2

474 ± 245

21.0

Maximum plasma concentration.

0-24

Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the

90 minute infusion.

Terminal elimination half-life

area

Volume of distribution of terminal elimination phase.

Total systemic clearance.

Plasma specimens collected for 24 hours following the end of the 90 minute infusion.

Plasma specimens collected for 48 hours following the end of the 90 minute infusion. Because of

the longer collection period, these values provide a more accurate reflection of the terminal.

elimination half-lives of irinotecan hydrochloride and SN-38.

In vitro studies indicate that irinotecan hydrochloride exhibits moderate plasma protein

binding

(30%

bound).

SN-38

highly

bound

human

plasma

proteins

(approximately 95% bound). The plasma protein to which irinotecan hydrochloride and

SN-38 predominantly binds is albumin.

Biotransformation

The complete disposition of irinotecan hydrochloride has not been fully elucidated in

humans. Irinotecan hydrochloride is subject to extensive metabolic conversion by various

enzyme systems, including esterases to form the active metabolite SN-38, and uridine

diphosphate-glucuronosyl transferase 1A1 (UGT1A1) mediating glucuronidation of SN-38

to form the inactive metabolite SN-38 glucuronide (SN-38G). Irinotecan can also undergo

CYP3A4-mediated oxidative metabolism to several pharmacologically inactive oxidation

products, one of which can be hydrolysed by carboxylesterase to release SN-38.

Irinotecan is oxidised by cytochrome P450 isozyme 3A4 (CYP3A4) to yield two relatively

inactive

metabolites,

(7-ethyl-l0-[4-N-(5-aminopentanoic

acid)-l-piperidino]-

carbonyloxycamptothecin)

minor

metabolite,

(7-ethyl-l0-(4-amino-1-

piperidino)carbonyloxycamptothecin.

Elimination

The urinary excretion of irinotecan hydrochloride was 11% to 20% of the administered

dose; SN-38 <1% and SN-38G 3%. The cumulative biliary and urinary excretion of

irinotecan and its metabolites (SN-38 and SN-38G) over a period of 48 hours following

administration of irinotecan hydrochloride in two patients ranged from approximately 25%

(100 mg/m

) to 50% (300 mg/m

).

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Special Populations

Geriatric (> 65 years)

In studies where irinotecan hydrochloride was administered weekly, the terminal half-life of

irinotecan hydrochloride was 6.0 hours in patients who were 65 years or older and 5.5 hours

in patients younger than 65 years. Dose-normalised AUC

0-24

for SN-38 in patients who

were at least 65 years of age was 11% higher than in patients younger than 65 years. There

are no kinetic data on the use of the once-every-three-week dosage schedule in elderly

patients. A lower starting dose is recommended in patients 65 years and older based on

clinical toxicity experienced with this dosage regimen (see section 4.2).

Children and Adolescents

Information regarding the pharmacokinetics of irinotecan is not available.

Gender

The pharmacokinetics of irinotecan does not appear to be influenced by gender.

Hepatic Impairment

Irinotecan clearance is diminished in patients with hepatic dysfunction while relative

exposure to the active metabolite SN-38 is increased. The magnitude of these effects is

proportional to the degree of liver impairment as measured by elevations in serum total

bilirubin and transaminase concentrations (see section 4.2).

Renal Impairment

The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been

evaluated.

Pharmacokinetics in Combination Therapy

In a Phase I clinical study involving irinotecan hydrochloride, 5-fluorouracil (5-FU) and

leucovorin

(LV)

patients

with

solid

tumours

disposition

irinotecan

hydrochloride

substantially

altered

when

drugs

were

co-administered.

However, C

and AUC

0-24

of SN-38, the active metabolite, were reduced (by 14% and 8%

respectively) when irinotecan hydrochloride was followed by 5-FU and LV administration

compared with when irinotecan hydrochloride was given alone. Formal in vivo or in vitro

drug

interaction

studies

evaluate

the influence of irinotecan hydrochloride on the

disposition of 5-FU and LV have not been conducted.

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5.3 Preclinical safety data

Carcinogenicity

Long-term

carcinogenicity

studies

with

irinotecan

were

conducted.

Rats

were,

however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week

for 13 weeks (AUC about 1.3 times the values of patients administered 125 mg/m

) and

were then allowed to recover for 91 weeks. Under these conditions, there was a significant

linear trend with dose for the incidence of combined uterine horn endometrial stromal

polyps and endometrial stromal sarcomas.

Genotoxicity

Irinotecan

clastogenic

both

in

vitro

(Chinese

hamster

ovary

cells)

in

vivo

(micronucleus test in mice). Neither irinotecan nor SN-38 was mutagenic in the in vitro

Ames assay.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sorbitol,

Lactic acid,

Sodium hydroxide,

Hydrochloric acid,

Water for injection.

6.2 Incompatibilities

Other drugs should not be added to the infusion solution.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store at controlled room temperature 15° to 30°C. Protect from light. It is recommended

that the vial should remain in the carton until time of use.

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6.5 Nature and contents of container

CAMPTOSAR injection is available in single-dose amber polypropylene vials in the

following package sizes: 40 mg/2 mL*, 100 mg/5 mL* and 300 mg/15 mL.

These presentations are not currently supplied.

6.6 Special precautions for disposal and other handling

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7. MEDICINE SCHEDULE

Prescription Medicine

8. SPONSOR

Pfizer New Zealand Ltd

PO Box 3998

Auckland, New Zealand.

Toll Free number: 0800 736 363.

9. DATE OF FIRST APPROVAL

29 May 1997

10. DATE OF REVISION OF THE TEXT

10 October 2018

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Reformatting according to new New Zealand PI template

Section 3

Dose form added in line with TPDR

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Section 4.8

Updated in ADR-post marketing section for Infections and infestations

Section 6.2

Incompatibilities added in line with company held CDS.

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