Eloxatin

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Oxaliplatin 5 mg/mL
Available from:
sanofi-aventis new zealand limited
INN (International Name):
Oxaliplatin 5 mg/mL
Dosage:
5 mg/mL
Pharmaceutical form:
Concentrate for infusion
Composition:
Active: Oxaliplatin 5 mg/mL Excipient: Water for injection
Units in package:
Vial, glass, single dose, Type 1 clear glass, 50mg in 10mL pack, 10 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Johnson Matthey Pharmaceutical Materials
Therapeutic indications:
Oxaliplatin, in combination with fluorouracil and folinic acid, is indicated for adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of the primary tumour.
Product summary:
Package - Contents - Shelf Life: Vial, glass, single dose, Type 1 clear glass, 50mg in 10mL pack - 10 mL - 36 months from date of manufacture stored at or below 25°C. Do not freeze. - Vial, glass, single dose, Type 1 clear glass, 100mg in 20mL pack - 20 mL - 36 months from date of manufacture stored at or below 25°C. Do not freeze. - Vial, glass, single dose, Type 1 clear glass, 200mg in 40mL pack - 40 mL - 36 months from date of manufacture stored at or below 25°C. Do not freeze
Authorization number:
TT50-6503/2
Authorization date:
2004-06-14

ELOXATIN

Page 1 of 3

Eloxatin

®

Oxaliplatin concentrated solution for injection

CONSUMER MEDICINE INFORMATION

Please read this leaflet before you are given this medicine.

What is in this leaflet?

This leaflet answers some

common questions about Eloxatin

injection.

It does not contain all the

available information.

It does not take the place of

talking to your doctor or

pharmacist.

All medicines have benefits and

risks. Your doctor has weighed

the risks of using this medicine

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with this

medicine.

You may need to read it again.

What Eloxatin is used

Eloxatin is used to treat cancer of

the large intestine and rectum

(colorectal cancer). Eloxatin is

used with two other anti-cancer

drugs, fluorouracil (FU), and

folinic acid. The active ingredient

in Eloxatin is called oxaliplatin.

Cancer cells are normal cells

which have changed so that they

grow in an uncontrolled way.

Oxaliplatin works by interfering

with cancer cell growth. Because

of the similarities between cancer

cells and normal cells, anti cancer

drugs often have unwanted effects

on the body.

Your doctors have decided to

treat you with Eloxatin because

they believe that the benefit of

Eloxatin treatment will be greater

than the unwanted effects.

Many of the side effects from anti

cancer drugs are predictable and

can be prevented or lessened.

Your doctor and other staff will

take all of the precautions needed

to reduce the unwanted effects of

treatment.

Your doctor may have prescribed

this medicine for another reason.

Ask your doctor or pharmacist

if you have any questions about

why this medicine has been

prescribed for you.

This medicine is only available

with a doctor’s prescription.

Before you are given

When you must not be

given it

You should not be given

Eloxatin if you are allergic to

the active ingredient

oxaliplatin.

If you have had an allergic

reaction to oxaliplatin before, you

should not receive it again.

You must not be given Eloxatin

if you are pregnant or

breastfeeding.

Oxaliplatin may cause birth

defects if you are being treated

with it at the time of conception

or it is given to women who are

already pregnant. Adequate

contraception is required during

treatment with oxaliplatin. You

should discuss this with your

doctor. Nursing mothers are

advised not to breastfeed while

receiving oxaliplatin, as the effect

of breast milk from such patients

is unknown.

You must not be given it if you

have severe kidney disease.

Do not use it after the expiry

date (EXP) printed on the vial.

If you are given this medicine

after the expiry date has passed, it

may not work as well.

Before you start are given it

You must tell your doctor if:

You have had a reaction to

any other platinum compound,

You have severe kidney

disease,

You have nerve damage

(neuropathy),

you have any other medical

condition that he or she is not

aware of.

Taking other medicines

Tell your doctor or pharmacist

if you are taking any other

medicines, including any that

you buy without a prescription

from your pharmacy,

supermarket or health food

store.

Some medicines and Eloxatin

may interfere with each other.

Your doctor or pharmacist can

tell you what to do if you are

taking any of these medicines.

ELOXATIN

Page 2 of 3

How Eloxatin is given

Eloxatin will be given to you as

an infusion into one of your veins

(this is called an intravenous

infusion). The infusion will be

given over 2 - 6 hours.

The dose of Eloxatin is calculated

according to your body surface

area, which is calculated from

your weight and height. The usual

dose is 85mg/m² every two weeks

or 130mg/m

every three weeks.

Your doctor may change the dose

in some circumstances.

Each course of treatment is called

a cycle; your doctor will tell you

how many cycles you will

receive.

Eloxatin will be used with

fluorouracil (FU) and folinic acid.

Eloxatin

is not recommended in

children.

If you receive too much

(overdose)

Your doctor will decide what

dose of Eloxatin you need, and

this will be given under close

supervision, usually in a hospital

setting. The risk of an overdosage

in these circumstances is low. In

the event of an overdose

occurring, your doctor will decide

on the treatment necessary.

While you are being

given Eloxatin

Things you must do:

Avoid cold foods and drinks

and cover skin prior to

exposure to cold during or

within 48 hours following being

given oxaliplatin, since

neurological effects may be

brought on or worsened by

exposure to cold.

Contact your doctor

immediately if you develop

fever, particularly in

association with persistent

diarrhoea or evidence of

infection since this may indicate

low blood count.

Contact your doctor if

persistent vomiting, diarrhoea,

signs of dehydration, cough or

breathing difficulties or signs of

allergic reaction occur.

Visual disturbance is a rare side

effect of Eloxatin. Contact your

doctor if this happens to you,

and

do

not

drive

or

use

machinery until your vision is

clear.

Side Effects

Tell your doctor or nurse as

soon as possible if you do not

feel well while Eloxatin is being

given to you.

You should also tell your doctor

if you do not feel well between

courses of Eloxatin.

All medicines can have side

effects. It is important to

understand the side effects that

Eloxatin may cause, even though

you may not experience them. As

well as the predictable side effects

of Eloxatin, there are other effects

that occur much more rarely. If

you have any side effects or

notice anything unusual it is

important to inform your doctor

before your next treatment. Your

doctor will decide whether such

effects are because of your

treatment, and what action needs

to be taken.

This section explains the side

effects of Eloxatin, and some of

the checks made before each

treatment to prevent excessive

side effects.

Physical Condition

. Before

each treatment with Eloxatin

you will be examined for

any condition that may be

affected by chemotherapy

(for example, infection, or

loss of feeling). This will

include those conditions

caused by previous

treatment, those caused by

your disease, and those

caused by other things.

Loss of feeling.

Eloxatin can

affect nerves in the hands

and feet. This is common

soon after treatment and can

appear as tingling or

numbness in the fingers or

toes, and may be made

worse by cold temperatures

or by contact with cold

water or other cold objects

These symptoms often go

away between treatments,

but may last longer and get

worse with repeated

treatment. In some patients

the limbs may become weak

or painful. However, in most

patients these symptoms

improve after treatment is

stopped. Tell your doctor if

any of these things happen.

Your doctor will examine

you before treatment to see

if you are affected.

Nausea and Vomiting.

Severe nausea and vomiting

is uncommon with Eloxatin.

Mild nausea and vomiting is

more common. Medication

to prevent the sickness

caused by Eloxatin will be

given before treatment, and

may sometimes be continued

after treatment.

Diarrhoea.

Severe diarrhoea

may occur during treatment

with Eloxatin.

If you suffer from persistent or

severe diarrhoea or vomiting,

contact your doctor urgently

for treatment advice.

Low Blood Counts.

Eloxatin

can affect the body’s ability

to make blood cells. There

are three types of blood cells

checked

before

each

treatment;

platelets,

which

help control bleeding; white

blood cells, which help fight

infection;

blood

cells

which

move

oxygen

ELOXATIN

Page 3 of 3

around

body.

your

blood count is too low, your

treatment may be postponed,

or the dose reduced.

Tell

your

doctor

if

you

notice

any

bruising

or

abnormal

bleeding,

or

have

an

infection.

These

may

be

signs

of

a

low

blood count.

Difficulty swallowing.

Some

patients

experience

sudden, temporary feeling of

difficulty with swallowing or

breathing. This sensation, if

occurs,

usually

happens

during the infusion or within

hours after the infusion. It

triggered

swallowing

cold

drink.

Although

unpleasant,

this

feeling

does

last

long,

and goes away by itself.

Tell

your

doctor

if

this

happens to you.

Other known side effects of

Eloxatin are;

mucositis (sore lips or

mouth ulcers)

abdominal pain

constipation

anorexia

changes to liver function

mild hair loss (alopecia)

fever

inflammation around the

injection site

tiredness

skin rash

allergic reactions

conjunctivitis

altered taste

abnormal tongue sensation

nose bleeds

feeling of chest pressure

voice disturbance (rare)

loss of hearing (rare)

lung disorders (rare)

visual disturbance (rare)

infection in the body

(symptoms include

lightheadness, tiredness,

fever, feeling unwell)

abnormal clotting followed

by abnormal bleeding

abnormal changes to your

heart rate

duodenal ulcer

breakdown of muscle tissue

causing muscle fibres to be

released into the blood.

Symptoms include dark, red

urine, decreased urine

output, muscle stiffness or

aching

Other side effects not listed

above may also occur in some

patients. Tell your doctor if you

notice anything else that is

making you feel unwell.

After being given

Eloxatin

Storage

If you need to store Eloxatin

before you take it with you to

hospital, make sure it is stored in

a cool dry place where the

temperature does not exceed

C. Do not freeze.

Do not use it after the expiry

date (EXP) printed on the vial.

This is not all the information that

is available on Eloxatin. If you

have any more questions or are

not sure about anything ask your

doctor or pharmacist.

Product Description

What it looks like

Eloxatin comes as a concentrated

solution in a glass vial.

A box contains 1 vial.

Ingredients

Each Eloxatin vial contains the

active ingredient, oxaliplatin 50

mg or 100 mg.

Beside the active ingredient -

Eloxatin concentrated solution for

injection contains water for

injections.

Manufacturer

Eloxatin is supplied in New

Zealand by:

sanofi-aventis new zealand

limited

Level 8, James and Wells Tower

56 Cawley Street

Ellerslie

Auckland

New Zealand

This leaflet was updated in

December 2014

Registered Trademark

Eloxatin-ccdsv12-cmiv3-10dec14

New Zealand Data Sheet

September 2018

Eloxatin - Oxaliplatin

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DATA SHEET

1

PRODUCT NAME

Eloxatin 5mg/mL concentrated solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Eloxatin concentrate for injection is available in the following strengths:

Oxaliplatin 50 mg*

Oxaliplatin 100 mg*

Oxaliplatin 200 mg*

For the full list of excipients, see section 6.1.

Oxaliplatin is a white to off-white crystalline powder. It is slightly soluble in water, very

slightly soluble in methanol and practically insoluble in ethanol.

*Not marketed in New Zealand.

3

PHARMACEUTICAL FORM

Powder for injection: White to off-white freeze-dried powder in a clear glass vial

Concentrated solution for injection: A liquid contained in a clear glass vial

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Oxaliplatin, in combination with fluorouracil and folinic acid, is indicated for:

Adjuvant treatment of stage III (Duke’s C) colon cancer after complete resection of

the primary tumour

Treatment of advanced colorectal cancer

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September 2018

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4.2

DOSE AND METHOD OF ADMINISTRATION

Dose

In combination with fluorouracil and folinic acid the recommended dose for the treatment of

advanced

colorectal

cancer

mg/m

intravenously

repeated

every

weeks,

130mg/m

repeated every three weeks.

In combination with fluorouracil and folinic acid the recommended dose for adjuvant

treatment is 85 mg/m

intravenously repeated every two weeks for 12 cycles (6 months).

4.2.1

Dosage Modification

Prior to each treatment cycle, patients should be evaluated for toxicity and the dose of

oxaliplatin adjusted accordingly.

Neurological toxicity

If acute neurological reactions occur eg acute pharyngolaryngeal dysaesthesia, increase the

oxaliplatin infusion time from 2 hours to 6 hours. This decreases C

by 30% and may

lessen acute toxicities.

If sensory loss or paraesthesia persists longer than 7 days or interferes with function (grade 2

toxicity), reduce oxaliplatin dose by 25%.

If sensory loss or paraesthesia interferes with activities of daily living (grade 3 toxicity),

oxaliplatin should be discontinued.

Haematological Toxicity

If haematological toxicity (neutrophils < 1.5 x 10

/L or platelets < 75 x 10

/L) is present

before starting treatment or prior to the next course:

Delay treatment until neutrophil count is

1.5 x 10

/L and platelet count is

75 x

/L and

Reduce the 85mg/m

oxaliplatin dose to 75mg/m² every two weeks and FU dose by

20% (adjuvant treatment)

Reduce the 85mg/m

oxaliplatin dose to 65mg/m² every two weeks and FU dose by

20% (advanced treatment)

Reduce the 130mg/m

oxaliplatin dose to 100mg/m

every three weeks and FU dose

by 20% (advanced treatment)

Gastrointestinal Toxicity

If grade 3-4 gastrointestinal reactions occur, as assessed according to US

National Cancer

Institute

criteria:

Delay treatment until resolution of the adverse reactions and

Reduce the 85mg/m

oxaliplatin dose to 75mg/m² every two weeks and FU dose by

20% (adjuvant treatment)

New Zealand Data Sheet

September 2018

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Reduce the 85mg/m

oxaliplatin dose to 65mg/m² every two weeks and FU dose by

20% (advanced treatment)

Reduce the 130mg/m

oxaliplatin dose to 100mg/m

every three weeks and FU dose

by 20% (advanced treatment)

Toxicity associated with fluorouracil

Dose adjustments should also be made for fluorouracil associated toxicities (see relevant

product information).

Oxaliplatin should be administered before fluorouracil.

Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 mL of 5%

glucose injection.

Preparation and Administration:

SPECIAL PRECAUTIONS FOR ADMINISTRATION

DO NOT use any injection material containing aluminium

DO NOT administer undiluted

DO NOT mix or administer with sodium chloride injection or any other solution

containing chlorides

DO NOT mix with any other medication or administer simultaneously by the same

infusion line (in particular fluorouracil and folinic acid). A Y-tube may be used (see

Infusion)

USE ONLY the recommended diluents (see below).

Any reconstituted solution that shows evidence of precipitation should not be used and

should be destroyed.

Handling

As with other potentially toxic compounds, caution should be exercised when handling and

preparing oxaliplatin solutions.

The handling of this cytotoxic agent by health care personnel requires every precaution to

guarantee

protection

handler

their

surroundings.

essential

appropriate protective clothing, including protective goggles, mask and gloves. Pregnant

women must be warned to avoid handling cytotoxic agents. If oxaliplatin concentrate,

premixed

solution

infusion

solution

should

come

into

contact

with

skin,

mucous

membranes or eyes, wash immediately and thoroughly with water.

Preparation of Infusion Solution

Dilution Before Infusion

The concentrated solution

MUST

be further diluted in an infusion solution of 250-500 mL of

5% glucose injection. From a microbiological and chemical point of view, this infusion

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preparation should be used immediately. Inspect visually prior to use. Only clear solutions

without particles should be used. Contains no antimicrobial agent. The product is for single

use in one patient only. Discard any residue.

NEVER

use sodium chloride solution for

dilution.

Infusion

The administration of oxaliplatin does not require prehydration. Oxaliplatin diluted in 250 to

500 mL of a glucose 5% injection must be infused either by central venous line or peripheral

vein over 2 to 6 hours. When oxaliplatin is administered with fluorouracil, the oxaliplatin

infusion should precede that of fluorouracil.

Oxaliplatin

co-administered

with

folinic

acid

infusion

using

Y-tube

placed

immediately before the site of injection. The drugs should not be combined in the same

infusion bag. Folinic acid must be diluted using isotonic infusion solutions such as 5%

glucose solution but

NOT

sodium chloride solutions or alkaline solutions.

Flush the line after oxaliplatin administration.

While oxaliplatin has minimal to no vesicant potential, extravasation may result in local pain

and inflammation which may be severe and lead to complications especially when oxaliplatin

is infused through a peripheral vein. In case of oxaliplatin extravasation, the infusion must be

stopped immediately and the usual local symptomatic treatment initiated.

4.3

CONTRAINDICATION

Oxaliplatin is contraindicated in patients who:

have a known history of hypersensitivity

to oxaliplatin,

are pregnant,

are breast feeding,

have

myelosuppression

prior

starting

first

course,

evidenced

baseline

neutrophils < 1.5 x 10

/L and/or platelet count of < 75 x 10

have a peripheral sensory neuropathy with functional impairment prior to first course,

have severely impaired renal function (creatinine clearance less than 30 mL/min).

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

General

Oxaliplatin should be administered only by or under the supervision of an experienced

clinical oncologist.

In case of oxaliplatin extravasation, the infusion must be stopped immediately and the usual

local symptomatic treatment initiated.

For oxaliplatin combined with fluorouracil (with or without folinic acid), the usual dose

adjustments for fluorouracil toxicities should apply (see relevant Product Information).

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Allergic Reactions

Anaphylactic-like reactions to Eloxatin have been reported, and may occur within minutes of

Eloxatin administration. Patients with a history of allergic reactions to platinum compounds

should be monitored for allergic symptoms. In case of an anaphylactic-type reaction to

oxaliplatin, the infusion should be immediately discontinued and appropriate symptomatic

treatment initiated. Rechallenge with oxaliplatin is contraindicated.

Neurological Toxicity

Neurological

toxicity

(see

Section

4.8)

oxaliplatin

should

carefully

monitored,

especially if co-administered with other medications with specific neurological toxicity. A

neurological examination should be performed before initiation of each administration, and

periodically thereafter. It is not known whether patients with pre-existing medical conditions

associated with peripheral nerve damage have a reduced threshold for oxaliplatin induced

peripheral neuropathy.

If sensory loss or paraesthesia persists longer than 7 days or interferes with function (grade 2

toxicity), reduce oxaliplatin dose by 25%.

If sensory loss or paraesthesia interferes with activities of daily living (grade 3 toxicity),

oxaliplatin should be discontinued.

For patients who develop acute laryngopharyngeal dysaesthesias, during or within 48 hours

following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6

hours. To prevent such dysaesthesia, advise the patient to avoid exposure to cold and to

avoid ingesting cold food and/or beverages during or within 48 hours following oxaliplatin

administration.

Signs and symptoms of Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also

known as PRES, Posterior Reversible Encephalopathy Syndrome) could be headache, altered

mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not

with hypertension (see Section 4.8). Diagnosis of RPLS is based upon confirmation by brain

imaging.

Gastrointestinal Toxicity

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic anti-

emetic

therapy,

including

5-HT3

antagonists

corticosteroids.

Dehydration,

ileus,

intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused

by severe diarrhoea/emesis, particularly when combining oxaliplatin with fluorouracil.

Intestinal Ischaemia

Cases of intestinal ischaemia, including fatal outcomes, have been reported with oxaliplatin

treatment. In case of intestinal ischaemia, oxaliplatin treatment should be discontinued and

appropriate measures initiated (see Section 4.8).

Haematological Toxicity

Monitor haematological toxicity with a full blood count and white cell differential count prior

to starting therapy and before each subsequent course. Idiosyncratic haematological toxicity

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may occur, especially in patients who have received previous myelotoxic treatment. If

severe/life

threatening

diarrhoea,

severe

neutropenia,

febrile

neutropenia

severe

thrombocytopenia occur, oxaliplatin must be discontinued until improvement or resolution

and appropriate dose adjustments may apply.

Patients must be adequately informed of the risk of diarrhoea/emesis and neutropenia after

oxaliplatin/fluorouracil

administration

that

they

urgently

contact

their

treating

physician for appropriate management.

Infection

Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with

oxaliplatin, including fatal outcomes. If any of these events occurs, oxaliplatin should be

discontinued (see Section 4.8).

Disseminated intravascular coagulation (DIC)

DIC, including fatal outcomes, has been reported in association with oxaliplatin treatment. If

DIC is present, oxaliplatin treatment should be discontinued and appropriate treatment should

be administered (see Section 4.8).

Pulmonary Toxicity

Eloxatin has been associated with pulmonary fibrosis (0.7% of study patients), which may be

fatal. In the case of unexplained respiratory symptoms such as non-productive cough,

dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued

until further pulmonary investigations exclude an interstitial lung disease or pulmonary

fibrosis (see Section 4.8).

Haemolytic-uraemic syndrome (HUS)

Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (see Section 4.8).

Oxaliplatin should be discontinued at the first signs of any evidence of microangiopathic

haemolytic

anaemia,

such

rapidly

falling

haemoglobin

with

concomitant

thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or

LDH. Renal failure may be not reversible with discontinuation of therapy and dialysis may be

required.

Hepatic Toxicity

Reactions related to liver sinusoidal obstruction syndrome, including nodular regenerative

hyperplasia, have been reported (see Section 4.8). In the case of abnormal liver function test

results or portal hypertension which could not be explained by liver metastases, reactions

related to liver sinusoidal obstruction syndrome should be investigated, and very rare cases of

drug induced hepatic vascular disorders should be considered.

QT prolongation

QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade

de Pointes, which can be fatal (see Section 4.8). Caution should be exercised in patients with

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a history or a predisposition for prolongation of QT, those who are taking medicinal products

known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia,

hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, oxaliplatin treatment

should be discontinued (see Section 4.5 and Section 4.8).

Cardiac Disorders

Postmarketing reports with oxaliplatin use include acute coronary syndrome (including

myocardial infarction, coronary arteriospasm, and cardiac arrest). In case of acute coronary

syndrome, treatment with Eloxatin may need to be interrupted or discontinued based on the

individual benefit-risk assessment (see Section 4.8).

Postmarketing

reports

with

oxaliplatin

include

cardiac

arrhythmias

(including

bradyarrhythmia, tachycardia and atrial fibrillation). In case of cardiac arrhythmias, treatment

with Eloxatin may need to be interrupted or discontinued based on the individual benefit-risk

assessment (see Section 4.8).

Rhabdomyolysis

Rhabdomyolysis

been

reported

patients

treated

with

oxaliplatin,

including

fatal

outcomes. In case of muscle pain and swelling, in combination with weakness, fever or

darkened urine, oxaliplatin treatment should be discontinued. If rhabdomyolysis is confirmed,

appropriate

measures

should

taken.

Caution

recommended

medicinal

products

associated with rhabdomyolysis are administered concomitantly with oxaliplatin (see Section

4.5 and Section 4.8).

Duodenal ulcer

Oxaliplatin treatment can cause duodenal ulcer (DU) and potential complications, such as

duodenal ulcer haemorrhage and perforation, which can be fatal. In case of duodenal ulcer,

oxaliplatin treatment should be discontinued and appropriate measures taken (see Section

4.8).

Off-label route of administration

Do not use oxaliplatin intraperitoneally. Peritoneal hemorrhage may occur when oxaliplatin is

administered by intraperitoneal route (off-label route of administration).

Renal Impairment

Oxaliplatin has not been studied in patients with severe renal impairment. It is therefore

contraindicated in patients with severe renal impairment.

There is limited information on safety in patients with moderately impaired renal function,

and administration should only be considered after suitable appraisal of the benefit/risk for

the patient, however, treatment may be initiated at the normally recommended dose. In this

situation, renal function should be closely monitored and dose adjusted according to toxicity.

There is no need for dose adjustment in patients with mild renal dysfunction.

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Hepatic Insufficiency

Oxaliplatin has not been studied in patients with severe hepatic impairment. No increase in

oxaliplatin acute toxicities was observed in the subset of patients with abnormal liver

function tests at baseline. No specific dose adjustment for patients with abnormal liver

function tests was performed during clinical development.

Paediatric Population

Oxaliplatin is not recommended for use in children as safety and efficacy have not been

established in this group of patients.

Elderly

No increase in severe toxicities was observed when oxaliplatin was used as a single agent or

in combination with fluorouracil in patients over the age of 65. In consequence no specific

dose adaptation is required for elderly patients.

4.5

INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTION

In patients who have received a single dose of 85 mg/m

of oxaliplatin, immediately before

administration of fluorouracil, no change in the level of exposure to fluorouracil has been

observed. However, in patients dosed with fluorouracil weekly and oxaliplatin 130 mg/m

every 3 weeks, increases of 20% in fluorouracil plasma concentrations have been observed.

In vitro

little or no displacement of oxaliplatin binding to plasma proteins has been observed

with the following agents; erythromycin, salicylates, granisetron, paclitaxel, and sodium

valproate.

Oxaliplatin is incompatible with chloride containing solutions and basic solutions (including

fluorouracil),

therefore

oxaliplatin

should

mixed

with

these

administered

simultaneously via the same IV line. There is no data for compatibility with other drugs.

The lack of Cytochrome P450 mediated metabolism indicates that oxaliplatin is unlikely to

modulate

P450

metabolism

concomitant

medications

through

competitive

mechanism.

Caution is advised when oxaliplatin treatment is co-administered with other medicinal

products known to cause QT interval prolongation. In case of combination with such

medicinal products, the QT interval should be closely monitored (see Section 4.4).

Caution is advised when oxaliplatin treatment is administered concomitantly with other

medicinal products known to be associated with rhabdomyolysis (see Section 4.4

)

Advice to patients

Must

adequately

informed

risk

diarrhoea/emesis

neutropenia

after

oxaliplatin/fluorouracil

administration

that

they

urgently

contact

their

treating

physician for appropriate management.

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Patients and caregivers should be informed of the expected side effects of Eloxatin and, in

particular, patients should be advised to:

Avoid cold foods and drinks and cover skin prior to exposure to cold during or within

48 hours following oxaliplatin administration, since neurological effects may be

precipitated or exacerbated by exposure to cold.

Contact their doctor immediately if they develop fever, particularly in association

with persistent diarrhoea or evidence of infection since this may indicate low blood

count.

Contact their doctor if persistent vomiting, diarrhoea, signs of dehydration, cough or

breathing difficulties or signs of allergic reaction occur.

Paediatric population

Interaction studies have only been performed in adults.

4.6

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

Category D. Reproductive toxicity studies showed no teratogenic activity in rats or rabbits at

intravenous doses up to 6 and 9 mg/m²/day respectively (1/20 of the maximum recommended

clinical dose, based on body surface area). However, increased embryonic deaths, decreased

foetal weight and delayed ossifications were observed in rats. Related compounds with

similar mechanisms of action have been reported to be teratogenic. There are no adequate

and well- controlled studies in pregnant women. If this 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 foetus. Oxaliplatin is probably toxic to the human foetus at the

recommended therapeutic dose, and is therefore contraindicated during pregnancy.

with

other

cytotoxic

agents,

effective

contraceptive

measures

should

taken

potentially fertile patients prior to initiating chemotherapy with oxaliplatin.

Breast-feeding

There are no data on the excretion of oxaliplatin into milk of animals or humans. Oxaliplatin

is contraindicated in breast feeding women.

Fertility

In dogs dosed with oxaliplatin, a decrease in testicular weight accompanied with testicular

hypoplasia approaching aplasia was seen at doses ≥ 15 mg/m². However, no effects on

fertility were seen in male and female rats at doses up to 12 mg /m²/day for 5 days/cycle.

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Vision

abnormalities,

particular

transient

vision

loss

(reversible

following

therapy

discontinuation), may affect patient’s ability to drive and use machines. Therefore, patients

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should be warned of the potential effect of these events on the ability to drive or use

machines.

4.8

UNDESIRABLE EFFECTS

Table 1: FU/FA

Oxaliplatin in adjuvant treatment of colon cancer - EFC3313 (MOSAIC), all

grades and grade 3-4 toxicities - all cycles - % patients

Arm A

FOLFOX4

N=1108

Arm B

FU/FA

N=1111

All

Gr 3

Gr 4

All

Gr 3

Gr 4

Laboratory

Granulocytopenia

78.9

28.8

12.3

39.9

Thrombocytopenia

77.4

19.0

Anemia

75.6

66.9

Adverse events

Paraesthesia

92.0

12.4

15.6

Nausea

73.7

61.1

Diarrhoea

56.3

48.4

Vomiting

47.2

24.0

Stomatitis/mucositis

42.1

39.7

Skin disorder

31.5

35.5

Alopecia

30.2

28.1

Fever

27.3

12.2

Infection

25.2

24.9

Injection site reaction

11.1

10.4

Allergic reaction

10.3

Thrombosis/phlebitis

Neutropenic sepsis

Febrile neutropenia

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eloxatin-conc-ccdsv15-dsv6-06sep18

Table 2:FU/FA

Oxaliplatin in previously untreated patients with Advanced Colorectal Cancer, all grades and grade 3-4 toxicities - all cycles - %

patients

Incidence

of Toxicity

by patient

%

EFC 2961

EFC 2962

N9741

N=100

Control arm q 3w

FU CM 5-day

N=99

Oxaliplatin 125 q 3w

FU CM 5-day

N=208

Control arm q 2w

FU bolus + CIV

N=209

Oxaliplatin 85 q 2w

FU bolus + CIV

N=256

Irinotecan 125 q 6w

FU bolus x 4

weekly

N=259

FOLFOX4

Oxaliplatin 85 q

2w

FU bolus + CIV

All Gr.

Gr. 3-4

All Gr.

Gr. 3-4

All Gr.

Gr. 3-4

All Gr.

Gr. 3-4

All Gr.

Gr. 3-4

All Gr.

Gr. 3-4

Paraesthesias†

20.0

91.9

11.5

67.0

16.7

15.6

77.2

17.8

Laryngopharyngeal

dysesthesia

NA†

NA†

NA†

NA†

38.2

Neurosensory

NA†

NA†

NA†

NA†

12.0

Nausea

53.4

72.2

67.2

14.5

71.0

Vomiting

64.0

88.9

25.3**

29.3

54.1

43.4

13.3

40.9

Diarrhoea

49.0

85.9

43.4**

43.8

58.9

12.0

65.2

28.5

56.0

11.6

Stomatitis

59.0

61.6

10.1

35.6

44.0

25.0

37.5

Anaemia

74.0

83.8

80.8

85.2

28.1

27.0

Neutropenia

30.3

30.8

74.6

43.1

80.1

46.1***

82.2

54.1***

Thrombocytopenia

28.8

75.6

26.2

71.4

Fever without

neutropenia

19.0

12.1

14.9

33.0

16.2

Infection

27.9

31.6

Asthenia

21.6

23.4

Fatigue

12.9

58.2

10.5

70.3

Alopecia

19.2

17.7

44.1

37.5

Skin

38.0

39.4

32.2

28.7

75.0

91.9

23.1

46.4

17.4

22.0

47.5

21.6

29.2

Alk. phosphatase

85.0

14.0

82.8

19.2

39.9

56.5

16.2

Creatinine increase

26.0

NA: Not applicable

*nausea-vomiting are reported together in that study (WHO toxicity grading scale)

CIV – continuous intravenous infusion

** modified WHO toxicity grading scale

*** 14.8% febrile neutropenia reported in the IFL arm and 4.2% in the FOLFOX4 arm

†Various studies used different data convention. Break down data collection by laryngopharyngeal dysesthesia and neurosensory was not done in EFC2962.

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Note:

very common

1/10 (

10%)

common

1/100 and <1/10 (

1% and <10%)

uncommon

1/1000 and <1/100 (

0.1% and <1.0%)

rare

1/10,000 and <1/1000 (

0.01% and <0.1%)

very rare

<1/10,000 (<0.01%)

Infections and infestations

common:

Neutropenic sepsis, including fatal outcomes

uncommon:

Sepsis, including fatal outcomes

Blood and Lymphatic system disorders

Adjuvant

Advanced

very common:

Epistaxis, anaemia (all grades),

neutropenia (all grades),

thrombocytopenia (all grades)

Anaemia (all grades),

neutropenia (all grades),

thrombocytopenia (all grades)

common

Febrile neutropenia

Febrile neutropenia

rare

Disseminated intravascular

coagulation (DIC), including

fatal outcomes.

Disseminated intravascular

coagulation (DIC), including

fatal outcomes.

Autoimmune haemolytic

anaemia and thrombocytopenia

In both adjuvant and advanced cancer treatment, addition of oxaliplatin to fluorouracil and

folinic acid:

Substantially

increased

incidence

neutropenia

severe

neutropenia

(neutrophils < 1.0 x 10

/L) and

Substantially increased the incidence of thrombocytopenia (Table 1,Table 2).

Immune system disorders

Adjuvant

Advanced

very common:

Skin rash (particularly urticaria),

conjunctivitis, rhinitis

Skin rash (particularly urticaria),

conjunctivitis, rhinitis

common:

Bronchospasm, sensation of

chest pain, angioedema,

hypotension, anaphylactic shock

Bronchospasm, sensation of

chest pain, angioedema,

hypotension, anaphylactic shock

Metabolism and nutrition disorders

Very common:

Anorexia; Hyperglycemia

common:

hypocalcaemia

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Nervous system disorders

Adjuvant

Advanced

very common:

Sensory peripheral neuropathy,

dysgeusia (taste perversion)

Primarily sensory peripheral

neuropathy (eg loss of deep

tendon reflexes, dysaesthesia,

paraesthesia Lhermitte’s sign),

dysgeusia

common:

Pharyngolaryngeal dysaesthesia,

jaw spasm, abnormal tongue

sensation, feeling of chest

pressure

rare:

Dysarthria, Reversible Posterior

Leukoencephalopathy Syndrome

(RPLS, also known as PRES)

(see Section 4.4).

Neurological adverse reactions are the dose-limiting toxicity. A primarily sensory peripheral

neuropathy occurs in 85-95% of patients. These symptoms usually develop at the end of the

2-hour oxaliplatin infusion or within a few hours, abate spontaneously within the next hours

or days, and frequently recur with further cycles. They may be precipitated by or exacerbated

by exposure to cold temperatures or objects. They usually present as transient paraesthesia,

dysaesthesia and hypoaesthesia. There may be functional impairment such as difficulty in

executing fine movements. The duration of symptoms increases with the number of treatment

cycles. Symptoms usually recede between courses of treatment.

If symptoms persist or pain or functional impairment develops, the dose should be reduced or

treatment discontinued (see Section 4.2).

In the adjuvant setting, for a cumulative dose of 850 mg/m

(10 cycles) the risk of occurrence

of persistent symptoms is 10% and for a cumulative dose of 1020 mg/m

(12 cycles) the risk

of occurrence is 20%.

In the advanced setting, in EFC 2962, 16% of patients receiving oxaliplatin + FU/FA

developed paraesthesia and associated functional impairment lasting longer than two weeks,

after a median cumulative oxaliplatin dose of 874 mg/m². Two percent were withdrawn due

persisting

paraesthesia

(i.e.

persisting

between

treatment

cycles),

after

cumulative

oxaliplatin doses of 759-1100 mg/m².

In EFC2961, 13% developed parasthesia and functional impairment, with a median onset of 6

months or after a cumulative oxaliplatin dose of 1100 mg/m

In the majority of cases, the neurological signs and symptoms improve when treatment is

discontinued. Analysis of patients in EFC 2962 showed that of the 34 patients who

developed Grade 3 neurotoxicity (the maximum grade in that study), 25 (73.5%) had an

improvement of their symptoms in a median time of 13.2 weeks. Eight of the 34 patients

(23%) had complete resolution of their symptoms. The mean duration of the Grade 3

neurotoxicity was 13.6 weeks. The mean cumulative oxaliplatin dose at date of onset was

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913.6 mg/m² (range:169.7-1713.15 mg/m²) . The median follow-up time for these 34 patients

was 55.71 weeks.

An acute pharyngolaryngeal dysaesthesia syndrome occurs in 1% to 2% of patients. It often

occurs on exposure to cold and changes in temperature. It is characterised by subjective

sensations of dysphagia and dyspnoea, feeling of suffocation, without evidence of respiratory

distress (no cyanosis or hypoxia, laryngospasm or bronchospasm).

Other symptoms occasionally observed, particularly of cranial nerve dysfunction may be

either associated with other symptoms, or also may occur in isolation, such as ptosis,

diplopia,

aphonia/dysphonia/hoarseness,

sometimes

described

vocal

cord

paralysis,

abnormal

tongue

sensation

dysarthria,

sometimes

described

aphasia,

trigeminal

neuralgia/facial pain/eye pain, decrease of visual acuity, visual field disorders. In addition,

the following symptoms have been observed: jaw spasm/muscle spasm/muscle contractions –

involuntary/muscle

twitching/myoclonus,

coordination

abnormal/gait

abnormal/ataxia/balance disorders, throat or chest tightness/pressure/discomfort/pain.

Eye disorders and Ear and labyrinth disorders

Adjuvant

Advanced

common:

Conjunctivitis

uncommon:

Ototoxicity

rare:

Deafness, optic neuritis, loss of

visual acuity, visual field

disturbances, transient vision

loss (reversible following

therapy discontinuation).

Deafness, optic neuritis, loss of

visual acuity, visual field

disturbances, transient vision

loss (reversible following

therapy discontinuation).

Vascular Disorders

Adjuvant

Advanced

very common:

Epistaxis

Epistaxis

common:

Deep vein thrombosis,

thromboembolic events

(including pulmonary

embolism), hypertension

Deep vein thrombosis,

thromboembolic events

(including pulmonary

embolism), hypertension

Respiratory, thoracic and mediastinal disorders

Adjuvant

Advanced

very common

Cough

cough

common:

Rhinitis, dyspnoea, hiccups

hiccups

rare:

Acute interstitial lung disease

(sometimes fatal), pulmonary

fibrosis

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Gastrointestinal disorders

Adjuvant

Advanced

very common:

Diarrhoea, nausea, vomiting,

stomatitis, abdominal pain,

mucositis, constipation

Diarrhoea, nausea, vomiting,

stomatitis, abdominal pain,

mucositis, dehydration, ileus,

intestinal obstruction,

hypokalemia, metabolic

acidosis, constipation

common:

Dyspepsia, gastrointestinal

haemorrhage

Gastrointestinal haemorrhage

rare:

Pancreatitis

Colitis, including Clostridium

difficile diarrhoea

Pancreatitis

Dehydration,

ileus,

intestinal

obstruction,

hypokalemia,

metabolic

acidosis

renal

impairment

caused

severe

diarrhoea/emesis,

particularly

when

combining

oxaliplatin with fluorouracil (see Section 4.4)

Addition of oxaliplatin to fluorouracil and folinic acid:

Increased the incidence of severe nausea, vomiting, diarrhoea and stomatitis in the

adjuvant setting (Table 1) and substantially increased these effects in the advanced

cancer setting (Table 2).

Hepatobiliary disorders

Adjuvant

Advanced

very rare

Reactions related to liver

sinusoidal obstruction syndrome,

including peliosis hepatis,

nodular regenerative

hyperplasia, perisinusoidal

fibrosis. Clinical manifestations

may be portal hypertension

and/or increased transaminases.

Reactions related to liver

sinusoidal obstruction syndrome,

including peliosis hepatis,

nodular regenerative

hyperplasia, perisinusoidal

fibrosis. Clinical manifestations

may be portal hypertension

and/or increased transaminases.

Skin and subcutaneous tissue disorders

Adjuvant

Advanced

very common:

Alopecia, rash

common:

Alopecia, rash

Moderate alopecia has been reported in 2% of patients treated with oxaliplatin as a single

agent; the combination of oxaliplatin and fluorouracil did not increase the incidence of

alopecia observed with fluorouracil alone.

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Musculoskeletal and connective tissue disorders

Adjuvant

Advanced

very common:

Back pain*, arthralgia

* Back pain. If associated with haemolysis, which has been rarely reported, should be

investigated.

Renal and urinary disorders

Adjuvant

Advanced

common:

Altered renal function

very rare:

Renal tubular necrosis

In clinical and post-marketing setting:

very rare

– Acute tubular necrosis, acute interstitial

nephritis, and acute renal failure.

General disorders and administration site conditions

Adjuvant

Advanced

very common:

Infections, fever, rigors

(tremors), fatigue, asthenia,

injection site reactions

Infections, fever, rigors

(tremors) fatigue, asthenia,

injection site reactions

common:

Febrile neutropenia

Febrile neutropenia

Injection site reactions including local pain, redness, swelling and thrombosis have been

reported. Extravasation may also result in local pain and inflammation, which may be severe

and lead to complications including necrosis, especially when oxaliplatin is infused through a

peripheral vein.

Investigations

very common:

Increased bilirubin, elevation of transaminases and

alkaline phosphatases activities

Post marketing experience with frequency not known:

The following additional adverse events were observed following the marketing of Eloxatin

when used with various chemotherapy regimens:

Infections and infestations

Septic shock, including fatal outcomes

Blood and lymphatic system disorders

Haemolytic uremic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukemia

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Immune system disorders

Delayed hypersensitivity

Nervous system disorders

Convulsion, ischemic and hemorrhagic cerebrovascular disorder

Cardiac disorders

QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes,

which may be fatal. (see Section 4.4)

Acute coronary syndrome including myocardial infarction, coronary arteriospasm, and

cardiac arrest.

Cardiac arrhythmias including bradyarrhythmia, tachycardia and atrial fibrillation.

Respiratory, thoracic and mediastinal disorders

Laryngospasm, pneumonia and bronchopneumonia, including fatal outcomes

Gastrointestinal disorders

Intestinal ischaemia, including fatal outcomes (see Section 4.4).

Esophagitis

Duodenal ulcer, and complications, such as duodenal ulcer haemorrhage or perforation,

which can be fatal. (see Section 4.4).

Skin and subcutaneous tissue disorders

Hypersensitivity vasculitis

Injury, poisoning, and procedural complications

Fall and fall-related injuries

Musculoskeletal and connective tissue disorders

Rhabdomyolysis, including fatal outcomes (see Section 4.4)

Reporting of suspected adverse reactions

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

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

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

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4.9

OVERDOSE

There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse

events can be expected. Monitoring of haematological parameters should be initiated and

symptomatic treatment given.

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

Pharmacotherapeutic group: other antineoplastic agents, platinum compounds

ATC code: L01XA03

Oxaliplatin

designated

chemically

SP

-4-2]-(1

R

R

)-(cyclohexane-1,2-diamine-

N,N

´(oxalato(2-)-k

O

O

]platinum (II)

The empirical formula of oxaliplatin is C

Pt and its molecular weight is 397.3.

Oxaliplatin has the following chemical structure:

CAS Number: 61 825-94-3

Mechanism of action

Oxaliplatin is an antineoplastic drug belonging to a new class of platinum based compounds

in which the platinum atom is complexed with 1,2-diaminocyclohexane (dach) and an oxalate

group. Oxaliplatin is a single enantiomer, the Cis-[oxalato(trans-

-1,2-DACH) platinum].

Oxaliplatin exhibits a wide spectrum of both

in vitro

cytotoxicity and

in vivo

antitumour

activity in a variety of tumour model systems, including human colorectal cancer models.

Oxaliplatin also demonstrates

in vitro

in vivo

activity in various cisplatin resistant

models.

A synergistic cytotoxic action has been observed in combination with fluorouracil both

in

vitro

in vivo

Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show

that the aqua-derivatives resulting from the biotransformation of oxaliplatin interact with

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DNA to form both inter- and intra-strand cross links, resulting in the disruption of DNA

synthesis leading to cytotoxic and antitumour effects.

Clinical efficacy and safety

Adjuvant treatment of Stage III (Duke’s C) colon cancer

Use in Combination with fluorouracil and folinic acid (FU/FA)

EFC3313 (MOSAIC)

EFC3313 (MOSAIC) was an international, multicentre, open-label, randomised phase III

study comparing two treatment regimens (FOLFOX4 versus FU/FA) as adjuvant treatment of

Duke’s stage B2/C colon cancer. FOLFOX4 - Day 1; Oxaliplatin 85mg/m

as 2 hour

infusion, folinic acid 200 mg/m

over 2 hours, followed by a FU bolus of 400 mg/m

, then a

FU infusion of 600 mg/m

over 22 hours. Folinic acid and FU repeated on Day 2. FU/FA -

the same regimen without oxaliplatin. Both were repeated every two weeks. A total of 1108

patients were treated in the FOLFOX4 arm and 1111 in the FU/FA arm. The median number

of cycles received in both arms was 12.

In the ITT population, after a median of 4 years follow-up, patients treated with FOLFOX4

had significantly increased disease-free survival, the primary endpoint, compared to patients

treated with FU/FA (Table 3). In the sub-group analysis by disease stage, only patients with

Stage III disease had significantly increased disease-free survival. The trial was not powered

to show such a benefit with Stage II disease, but the trend indicated a small benefit is likely.

This benefit is not as great as in Stage III patients. The trial was not powered to show

significant benefit in overall survival.

Table 3: Disease Free Survival and Overall Survival – ITT population

Disease Stage

FOLFOX4

FU/FA

Hazard Ratio

[95% CI]

Disease-free Survival

- 4 year probability (%) of

Surviving disease-free [95% CI]

75.9

[73.4, 78.5]

(n=1123)

69.1

[66.3, 71.9]

(n=1123)

0.76

[0.65, 0.90]

85.1

[81.7, 88.6]

(n=451)

81.3

[77.6, 85.1]

(n=448)

0.80

[0.58, 1.11]

69.7

[66.2, 73.3]

(n=672)

61.0

[57.1, 64.8]

(n=675)

0.75

[0.62, 0.90]

Overall Survival*

- 4 year probability (%) of

Surviving [95% CI]

84.0

[81.7, 86.3]

(n=1123)

82.4

[80.0, 84.8]

(n=1123)

0.89

[0.72, 1.09]

91.0

[88.1, 93.9]

(n=451)

91.1

[88.3, 93.9]

(n=448)

0.98

[0.63, 1.53]

79.2

[76.0, 82.5]

(n=672)

76.6

[73.2, 80.0]

(n=675)

0.86

[0.68, 1.08]

* The trial was not powered to show significant benefit in overall survival.

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Treatment of Advanced Colorectal Cancer

Use in Combination with fluorouracil and folinic acid (FU/FA)

A total of 1312 patients have been enrolled in 3 pivotal trials, for untreated (EFC7462/N9741,

EFC 2962) and pretreated patients (EFC 2964). These studies evaluated the efficacy of

oxaliplatin at the same dose intensity (85 mg/m²/2 weeks) when added to different FU/FA

doses and regimens, in terms of overall survival, progression free survival and tumour

response.

EFC 7462/N9741

was a multicentre open-label randomised, 3-arm phase III study of

irinotecan and FU/LV (IFL), or oxaliplatin and irinotecan (IROX), or oxaliplatin and FU/LV

(FOLFOX4) as initial treatment of patients with advanced colorectal cancer. Therapy

consisted of 2-week FOLFOX4, 6-week IFL, or 3-week IROX treatment cycles.

A total of 795 patients were enrolled and 773 treated from May 1999 in 301 centres in the

United States and Canada.

Treatment arms – FOLFOX4 Day 1: oxaliplatin 85 mg/m

over 2 hours, folinic acid 200

mg/m

over 2 hours, followed by a FU bolus of 400 mg/m

, then a FU infusion of 600 mg/m

over 22 hours. Folinic acid and FU repeated on Day 2. Cycle repeated every 2 weeks.

IFL Day 1: irinotecan 125 mg/m

over 90 minutes, folinic acid 20 mg/m

over 15 minutes or

IV push, FU bolus of 500 mg/m

weekly x 4. Cycle repeated every 6 weeks.

IROX Day 1: oxaliplatin 85 mg/m

over 2 hours, irinotecan 200 mg/m

over 30 minutes.

Cycle repeated every 3 weeks.

This study has demonstrated a statistically significant longer TTP (time to progression) and

OS (overall survival), and a significantly higher overall RR (response rate) for oxaliplatin in

combination with bolus/infusional FU/LV (FOLFOX4) compared with the IFL control arm.

The IROX arm has a significantly longer OS compared with the IFL arm, while TTP and RR

on the IROX arm were not significantly different from the IFL arm. Median durations of

treatment

each

group

were

weeks

IFL,

FOLFOX4

IROX

(respectively)

Table 4: Summary of time to progression – ITT population

EFC7462/N9741

Time to Progression

IFL

N = 264

FOLFOX4

N = 267

IROX

N = 264

Number of progressors n (%)

216 (81.8)

221 (82.8)

236 (89.4)

Median TTP (months)

95% confidence interval

(6.0-7.5)

(7.8-9.8)

(5.8-7.6)

P-value (Log-Rank Test)

FOLFOX4 vs. IFL: P=0.0014

IROX vs. IFL: P=0.8295

Hazard Ratio (95% confidence interval)

FOLFOX4 vs. IFL: 0.74 (0.61-0.89)

IROX vs. IFL: 1.02 (0.85-1.23)

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Table 5: Summary of overall survival – ITT population

EFC7462/N9741

Overall Survival

IFL

N = 264

FOLFOX4

N = 267

IROX

N = 264

Number of deaths n (%)

192 (72.7)

155 (58.1)

175 (66.3)

Median survival (months)

14.6

19.4

17.6

95% confidence interval

(12.4-16.7)

(17.9-21.0)

(15.8-19.6)

P-value (Log-Rank Test)

FOLFOX4 vs. IFL: P<0.0001

IROX vs. IFL: P=0.0252

Hazard Ratio (95% confidence interval)

FOLFOX4 vs. IFL: 0.65 (0.53-0.80)

IROX vs. IFL: 0.79 (0.65-0.97)

Table 6: Summary of confirmed overall response – Patients (N, %) with measurable disease

EFC7462/N9741

Overall Response

IFL

N = 212

FOLFOX4

N = 210

IROX

N = 215

Complete and partial response

69 (32.5)

95 (45.2)

74 (34.4)

95% confidence interval

(26.2-38.9)

(38.5-52.0)

(28.1-40.8)

Complete response

5 (2.4)

13 (6.2)

7 (3.3)

Partial response

64 (30.2)

82 (39.0)

67 (31.2)

Regression

3 (1.4)

1 (0.5)

Stable disease

94 (44.3)

75 (35.7)

86 (40.0)

P-value (Chi-Squared Test)

FOLFOX4 vs. IFL: P< =0.0075

IROX vs. IFL: P=0.6820

Patients with measurable disease at randomisation that became too small to measure during the study were classified as

regression and not partial response in this study

Table 7: Number of deaths – Treated patients N (%)

EFC7462/N9741

IFL

N = 256

FOLFOX4

N = 259

IROX

N = 258

Number of deaths within 30 days of last dose

12 (4.7)

8 (3.1)

8 (3.1)

Number of deaths within 60 days of first dose

13 (5.1)

6 (2.3)

8 (3.1)

Number of deaths during the entire study

189 (73.8)

149 (57.5)

170 (65.9)

EFC 2962

was a multinational multicentre randomised phase III study in previously untreated

patients, comparing two-weekly fluorouracil bolus plus infusion and high dose folinic acid

(FU/FA

regimen:

folinic

acid

mg/m

over

hours,

followed

FU bolus of 400 mg/m

, then a FU infusion of 600 mg/m

over 22 hours. Repeated on Day 2.)

to the same regimen combined with oxaliplatin at the dosage of 85 mg/m² every two weeks. A

total of 420 patients were enrolled and 417 treated from August 1995 to July 1997 in 35

centres from 9 countries. The median number of treatment cycles was 12 in the FU/FA plus

oxaliplatin group and

11 in the

FU/FA

group. Confirmed responses after independent

radiological review (intent to treat analysis n = 420) are as shown in Table 8.

The FU/FA + oxaliplatin group had a statistically significant greater response rate and longer

progression free survival. There was no significant difference in overall survival between the

two groups, however, the study was not powered to detect a difference in overall survival.

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Additionally, in both groups, post-study treatment with other agents may have influenced

survival.

EFC 2964

an open label multicentre study in which patients

whose disease had

progressed

fluorouracil/folinic

acid

regimens

continued

same

fluorouracil/folinic acid regimen with the addition of oxaliplatin 85 mg/m

two weekly. The

two study regimens were; Regimen 1: Day 1; folinic acid 200 mg/m

over 2 hours, followed

by a FU bolus of 400 mg/m

, then a FU infusion of 600 mg/m

over 22 hours. Repeated on

Day 2.

Regimen 2: folinic acid 500 mg/m

over 2 hours, followed by a FU infusion of 1500 mg/m

over 22 hours, repeated on Day 2.

The results were as shown in Table 9.

EFC 2961

was a multicentre, randomised, phase III study in previously untreated patients,

comparing FU/FA administered as a chronomodulated infusion ( FU 3500 mg/m

and folinic

acid 1500 mg/m

over 5 days, with peaks at 4am) to the same regimen plus oxaliplatin

125 mg/m

given as a flat infusion. The regimen was repeated three weekly. Efficacy results

are shown in Table 10.

Table 8 (EFC 2962)

FU/FA + Oxp

n = 210

FU/FA

n = 210

Difference

Objective Response Rate

[95% CI]

Complete

Partial

49.0

[42, 56]

47.6

21.9

[16,27]

21.4

p = 0.0001

Median progression free survival

(months)

[95% CI]

[7.2, 8.8]

[5.5, 6.5]

p = 0.0003

(log rank)

Median survival time (months)

[95% CI]

[ 14.7, 18.2 ]

14.7

[13.7, 18.2 ]

p= 0.109

(log rank)

Table 9 (EFC 2964)

Regimen 1

n =57

Regimen 2

n = 40

All Treated Patients

n = 97

Confirmed Responses

n(%) [95% CI]

Expert assessment

Investigator assessment

13 (23%) [13-36]

11 (19%) [10-32]

7 (18%) [7-33]

10 (25%) [13-41]

20 (21%) [13-30]

21 (22%) [14-31]

Median progression free survival

(months)

[95% CI]

[3.1 - 5.7]

[3.0 - 5.5]

[3.4 - 5.5]

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Median overall survival (months)

[95% CI]

11.1

[8.3 -13.0]

10.5

[8.6 - 13.4]

11.0

[9.1 - 12.9]

1. Response rate assessed according to WHO-UICC criteria.

2. Independent expert review.

Table 10 (EFC 2961)

FU/FA + Oxp

n = 100

FU/FA

n = 100

Difference

Objective Response Rate

[95% CI]

Complete

Partial

[24, 44]

[6, 20]

p < 0.001

Median progression free survival

(months) [95% CI]

[6.7, 9.1]

[3.5, 6.7]

p = 0.045

(log rank)

Median survival (months)

[95% CI]

17.6

[13.1, 22.1]

19.4

[15.3, 30.5]

p = 0.82

(log rank)

5.2

PHARMACOKINETIC PROPERTIES

Absorption

pharmacokinetics

individual

active

compounds

have

been

determined.

pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and

inactive platinum species, following a two hour infusion of oxaliplatin at 130 mg/m² every

three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m

every two weeks for 1 to 3 cycles

are as follows:

Summary

Platinum

Pharmacokinetic

Parameter

Estimates

Ultrafiltrate

Following

Multiple Doses of Oxaliplatin at 85 mg/m

Every Two Weeks or at 130 mg/m

Every Three

Weeks

Dose

C

max

µg/mL

AUC

0-48

µg.h/mL

AUC

µg.h/mL

t

1/2

h

t

1/2

h

t

1/2

h

V

ss

L

CL

L/h

85 mg/m

2

Mean

0.814

4.19

4.68

0.43

16.8

17.4

0.193

0.647

1.40

0.35

5.74

6.35

130 mg/m

2

Mean

1.21

8.20

11.9

0.28

16.3

10.1

0.10

2.40

4.60

0.06

2.90

19.0

3.07

Mean AUC

0-48

and C

values were determined on Cycle 3 (85 mg/m

) or Cycle 5 (130 mg/m

Mean AUC, V

, and CL values were determined on Cycle 1.

, AUC, AUC

0-48

and CL values were determined by non-compartmental analysis.

were determined by compartmental analysis (Cycles 1-3 combined).

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Distribution

At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic

circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the

urine. Irreversible binding to red blood cells and plasma, results in half-lives in these matrices

that are close to the natural turnover of red blood cells and serum albumin. No accumulation

was observed in plasma ultrafiltrate following 85 mg/m

every two weeks or 130 mg/m

every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-

subject variability is generally low.

Biotransformation

Biotransformation

in vitro

is considered to be the result of non-enzymatic degradation and

there is no evidence of cytochrome P450 mediated metabolism of the diaminocyclohexane

(DACH) ring.

Oxaliplatin

undergoes

extensive

biotransformation

patients,

intact

drug

detectable

plasma

ultrafiltrate

hour

infusion.

Several

cytotoxic

biotransformation products including the monochloro, dichloro and diaquo DACH platinum

species have been identified in the systemic circulation together with a number of inactive

conjugates at later time points.

Excretion

Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following

administration. By day 5, approximately 54% of the total dose was recovered in the urine

and < 3% in the faeces.

A significant decrease in clearance of ultrafilterable platinum from 17.6

2.18 L/h to 9.95

1.91 L/h in renal impairment (creatinine clearance 12 – 57 mL/min) was observed together

with a statistically significant decrease in distribution volume from 330

40.9 to 241

36.1

L. The effect of severe renal impairment on platinum clearance has not been evaluated.

5.3

PRECLINICAL SAFETY DATA

Oxaliplatin was shown to be mutagenic and clastogenic in mammalian test systems

in vitro

in vivo

. The carcinogenic potential of oxaliplatin has not been studied, but compounds

with similar mechanisms of action and genotoxicity profiles have been reported to be

carcinogenic. Oxaliplatin should be considered a probable carcinogen.

6

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Eloxatin concentrated solution for injection also contains water for injections.

6.2

INCOMPATIBILITIES

Refer to Section 4.5 – Interactions with other medicines and other forms of interactions

New Zealand Data Sheet

September 2018

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eloxatin-conc-ccdsv15-dsv6-06sep18

6.3

SHELF LIFE

36 months

6.4

SPECIAL PRECAUTIONS FOR STORAGE

Store below 30ºC. Do not freeze.

6.5

NATURE AND CONTENTS OF CONTAINER <AND SPECIAL EQUIPMENT FOR

USE, ADMINISTRATION OR IMPLANTATION>

Eloxatin

sterile

concentrated

solution

infusion,

available

mg/10

mL*,

100 mg/20 mL* and 200mg/40mL* vials.

*Not marketed in New Zealand.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

All materials that have been used for reconstitution, for dilution and administration must be

destroyed according to local statutory requirements

7

MEDICINE SCHEDULE

Prescription Only medicine

8

SPONSOR

sanofi aventis new zealand limited

Level 8

56 Cawley Street, Ellerslie

Auckland

Toll free Number (medical information): 0800 283 684

9

DATE OF FIRST APPROVAL

2nd February 2006

10

DATE OF REVISION OF THE TEXT

03 September 2018

New Zealand Data Sheet

September 2018

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Page | 26

eloxatin-conc-ccdsv15-dsv6-06sep18

SUMMARY TABLE OF CHANGES

Section Changed

Summary of new information

2

Editorial changes

4.2

Editorial changes

4.4

Additional precautions added

4.8

Additional adverse events added

6.5

Editorial changes

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