ERLOTINIB SANDOZ erlotinib 100 mg tablet blister pack

Australia - English - Department of Health (Therapeutic Goods Administration)

Buy It Now

Active ingredient:
erlotinib hydrochloride
Available from:
Sandoz Pty Ltd
Authorization status:
Registered
Authorization number:
326624

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[MEDICINE NAME]

ERLOTINIB SANDOZ

®

erlotinib hydrochloride

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Erlotinib Sandoz

tablets. It does not contain all the

available information.

It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking Erlotinib

Sandoz tablets 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 the medicine.

You may need to read it again.

What Erlotinib Sandoz

is used for

Erlotinib Sandoz contains the active

ingredient erlotinib.

Erlotinib Sandoz is used for the

treatment of non-small cell lung

cancer (NSCLC). It can be given

before or after initial chemotherapy if

your cancer has specific mutations in

a protein called epidermal growth

factor receptor (EGFR). It can also

be given later on when initial

chemotherapy has not worked.

Erlotinib Sandoz is also used in

combination with gemcitabine for the

treatment of pancreatic cancer.

Erlotinib Sandoz belongs to a group

of medicines called anti-neoplastic

(or anti-cancer) agents which are

used to treat cancer.

Erlotinib Sandoz prevents the activity

of the EGFR protein. This protein is

known to be involved in the growth

and spread of cancer cells.

Your doctor may have prescribed

Erlotinib Sandoz for another purpose.

Ask your doctor if you have any

questions about why Erlotinib

Sandoz has been prescribed for

you.

Erlotinib Sandoz is not addictive.

This medicine is available only with

a doctor's prescription.

Before you take

Erlotinib Sandoz

When you must not take it

Do not take Erlotinib Sandoz if:

1.

you have had an allergic

reaction to erlotinib or any

ingredients listed at the end of

this leaflet

Some symptoms of an allergic

reaction may include:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue

or other parts of the body

rash, itching or hives on the skin

2.

the package is torn or shows

signs of tampering

3.

the expiry date (EXP) printed

on the pack has passed

If you take this medicine after the

expiry date has passed, it may not

work as well.

If you are not sure if you should be

taking Erlotinib Sandoz, talk to

your doctor.

Use in children

Do not give Erlotinib Sandoz to

children.

Safety and effectiveness in patients

less than 18 years of age have not

been established.

Use in elderly

Reduction in dose is not required for

elderly patients.

Before you start to take it

Your doctor must know about all the

following before you start to take

Erlotinib Sandoz.

Tell your doctor if:

1.

you are pregnant or plan to

become pregnant

Erlotinib Sandoz may be harmful

to an unborn baby when taken by

a pregnant woman. It is not

recommended that you take

Erlotinib Sandoz while you are

pregnant.

If you are a woman who could

become pregnant use adequate

contraception during treatment,

and for at least 2 weeks after

taking the last tablet.

If you become pregnant while

you are being treated with

Erlotinib Sandoz, tell your doctor

immediately.

2.

you are breast-feeding or plan

to breast-feed

It is not known whether erlotinib

passes into breast milk. It is not

recommended that you breast-

feed while taking Erlotinib

ERLOTINIB SANDOZ

Sandoz and for at least 2 weeks

after final dose

3.

you have liver problems

It is not known whether Erlotinib

Sandoz has a different effect if

your liver is not functioning

normally.

4.

you have kidney problems

5.

you have a history of stomach

ulcers or inflammation of the

bowel wall

6.

you are allergic to any other

medicines, foods, dyes or

preservatives

7.

you cannot tolerate lactose

If you have not told your doctor

about any of the above, tell them

before you start taking Erlotinib

Sandoz.

Taking other medicines

Tell your doctor if you are taking

any other medicines including any

that you have bought without a

prescription from a pharmacy,

supermarket or healthfood shop.

Some medicines may interfere with

Erlotinib Sandoz. These medicines

include:

medicines used to treat heartburn,

indigestion and ulcers, such as

antacids, H

antagonists (e.g.

ranitidine) and proton pump

inhibitors (e.g. omeprazole)

medicines used to treat HIV

infection such as atazanavir,

indinavir, ritonavir and saquinavir

medicines used to treat epilepsy

such as carbamazepine,

phenobarbital (also known as

phenobarbitone), phenytoin and

midazolam

medicines used to treat bacterial

infections such as ciprofloxacin,

clarithromycin, erythromycin,

rifampicin and rifabutin

corticosteroids, a group of

medicines used to treat

inflammation

medicines used to treat fungal

infections such as itraconazole,

voriconazole and ketoconazole

midazolam, a medicine used to

cause drowsiness before an

operation

non-steroidal anti-inflammatory

medicines (NSAIDs), medicines

used to relieve pain, swelling and

other symptoms of inflammation,

including arthritis

statins, a group of medicines used

to lower cholesterol

other medicines used to treat

cancer

These medicines may be affected by

Erlotinib Sandoz, or may affect how

well it works. You may need to take

different amounts of your medicine,

or you may need to take different

medicines. Your doctor will advise

you.

There are some medicines that may

still be taken with Erlotinib Sandoz

but may require close supervision by

your doctor. These medicines

include:

warfarin, a medicine used to

prevent blood clots

Your doctor will need to regularly

monitor you with blood tests.

Your doctor or pharmacist has more

information on medicines to be

careful with or avoid while taking

Erlotinib Sandoz.

How to take Erlotinib

Sandoz

How much to take

Take Erlotinib Sandoz exactly as

your doctor has prescribed.

Your doctor will tell you how many

Erlotinib Sandoz tablets to take each

day.

For non-small-cell lung cancer, the

usual dose is one 150 mg tablet each

day.

For pancreatic cancer, given in

combination with gemcitabine, the

usual dose is one 100 mg tablet each

day.

How to take it

Swallow the tablets whole with a

glass of water.

Do not chew the tablets.

When to take it

Take Erlotinib Sandoz tablets:

at least 1 hour before you eat or

at least 2 hours after you have

eaten

Do not take Erlotinib Sandoz with

food.

How long to take it

The duration of treatment with

Erlotinib Sandoz varies, depending

on the nature of your illness and your

individual response to the treatment.

Continue taking Erlotinib Sandoz

until your doctor tells you to stop.

If you forget to take it

Do not take an extra dose. Wait

until the next dose and take your

normal dose then.

Do not try to make up for the dose

that you missed by taking more

than one dose at a time.

If you are not sure what to do, ask

your doctor or pharmacist.

If you take too much

(overdose)

Immediately telephone your doctor

or the Poisons Information Centre

(telephone 13 11 26) for advice, or

go to Accident and Emergency at

the nearest hospital, if you think

that you or anyone else may have

taken too much Erlotinib Sandoz.

Do this even if there are no signs of

discomfort or poisoning.

You may need urgent medical

attention.

Keep telephone numbers for these

places handy.

ERLOTINIB SANDOZ

If you are not sure what to do,

contact your doctor or pharmacist.

While you are taking

Erlotinib Sandoz

Things you must do

Tell all doctors, dentists and

pharmacists who are treating you

that you are taking Erlotinib

Sandoz.

Tell your doctor if you become

pregnant while taking Erlotinib

Sandoz.

Tell your doctor if, for any reason,

you have not taken your medicine

exactly as prescribed.

Otherwise, your doctor may think

that it was not effective and change

your treatment unnecessarily.

Tell your doctor if you feel the

tablets are not helping your

condition.

Be sure to keep all of your

appointments with your doctor so

that your progress can be checked.

Things you must not do

Do not stop taking Erlotinib

Sandoz or change the dose without

first checking with your doctor.

Do not let yourself run out of

medicine over the weekend or on

holidays.

Do not give Erlotinib Sandoz to

anyone else even if they have the

same condition as you.

Do not take any other medicines

whether they require a

prescription or not without first

telling your doctor or consulting

with a pharmacist.

Smokers should stop smoking

while taking Erlotinib Sandoz as

blood levels of Erlotinib Sandoz

may be reduced.

Things to be careful of

It is not known if Erlotinib Sandoz

will affect your ability to drive or use

machines.

Be careful driving or operating

machinery until you know how

Erlotinib Sandoz affects you.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking Erlotinib

Sandoz.

Erlotinib Sandoz helps people with

non-small cell lung cancer and

pancreatic cancer but it may have

unwanted side effects.

All medicines can have side effects.

Sometimes they are serious, most of

the time they are not. You may need

medical treatment if you get some of

the side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor if you notice any

of the following and they worry

you:

rash

diarrhoea

your doctor may need to treat you

with a medicine for this (e.g.

loperamide)

tiredness

loss of appetite

weight loss

difficulty in breathing

cough

infection

nausea or vomiting

dehydration. Signs of dehydration

include dry skin, dark coloured

urine, thirst, weakness or fatigue

and loss of appetite

stomach pain or discomfort or

belching after eating

itching

dry skin

acne

tear in the skin

folliculitis (infection of the hair

roots)

unusual hair loss or thinning

conjunctivitis, discharge with

itching of the eyes and crusty

eyelid or swollen runny eyes

irritation or feeling of having

something in the eye

inflammation of the eye,

including pain or redness,

sensitivity to light or reduced

vision

nose bleeds

nail bed infection or swelling

around the nails

headache

fever

rigors or shaking

depression

numbness or weakness of the

arms and legs

These are the more common side

effects of Erlotinib Sandoz that you

are likely to notice. Your doctor will

tell you more about them. Your

doctor may also recommend that you

change the dose of Erlotinib Sandoz

that you are taking if you experience

any of the above side effects.

Tell your doctor immediately if

you notice any of the following:

mouth irritation, sore mouth,

mouth ulcers or cold sores

persistent cough

infection, fever, chills

These may be serious side-effects.

Your doctor may interrupt your

Erlotinib Sandoz treatment.

Tell your doctor immediately or go

to Accident and Emergency at

your nearest hospital if you notice

any of the following:

shortness of breath or difficulty

breathing with cough and/or

fever.

ERLOTINIB SANDOZ

severe stomach pain or

discomfort

severe or persistent diarrhoea,

nausea, vomiting or loss of

appetite

vomiting blood or material that

looks like coffee grounds,

bleeding from your back passage,

black sticky bowel motions

(stools), bloody diarrhoea

tongue and/or facial swelling

hives

wheezing

blisters on your skin, especially

severe blisters and bleeding in the

lips, eyes, mouth, nose and

genitals

painful red areas of skin, large

blisters and/or peeling of layers of

skin, accompanied by fever and

chills, aching muscles and

generally feeling unwell

yellowing of the skin and eyes

dark coloured urine

These may be very serious side

effects. You may need urgent

medical attention.

This is not a complete list of all

possible side effects. Others may

occur in some people and there may

be some side effects not yet known.

Tell your doctor if you notice

anything else that is making you

feel unwell, even if it is not on this

list.

Ask your doctor or pharmacist if

you don't understand anything in

this list.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

After taking Erlotinib

Sandoz

Storage

Keep your tablets in their

container until it is time to take

them.

If you take the tablets out of their

container they may not keep well.

Keep Erlotinib Sandoz in a cool

dry place where the temperature

stays below 30°C.

Do not store it, or any other

medicine, in a bathroom or near a

sink.

Do not leave it in the car or on

window sills.

Heat and dampness can destroy some

medicines.

Keep Erlotinib Sandoz where

young children cannot reach it.

A locked cupboard at least one-and-

a-half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking Erlotinib Sandoz, or the

medication has passed its expiry

date, ask your pharmacist what to

do with any tablets that are left

over. Do not throw out your

medicine into the general

household rubbish or flush it down

the toilet

Product description

Erlotinib Sandoz 25 mg film-coated

tablet contains erlotinib

hydrochloride equivalent to 25 mg

erlotinib.

Erlotinib Sandoz 50 mg film-coated

tablet contains erlotinib

hydrochloride equivalent to 50 mg

erlotinib.

Erlotinib Sandoz 100 mg film-coated

tablet contains erlotinib

hydrochloride equivalent to 100 mg

erlotinib.

Erlotinib Sandoz 150 mg film-coated

tablet contains erlotinib

hydrochloride equivalent to 150 mg

erlotinib.

Each tablet strength comes in packs

of 30 tablets.

Not all presentations may be

marketed.

What it looks like

Erlotinib Sandoz 25 mg film-

coated tablets are white to

yellowish, round, biconvex film-

coated tablets with "25" engraved

on one side.

Erlotinib Sandoz 50 mg film-

coated tablets are white to

yellowish, round, biconvex film-

coated tablets with “50” engraved

on one side.

Erlotinib Sandoz 100 mg fim-

coated tablets are white to

yellowish, round, biconvex film-

coated tablets with

"100"engraved on one side.

Erlotinib 150 mg film-coated

tablets are white to yellowish,

round, biconvex film-coated

tablets with "150" engraved on

one side.

Ingredients

Active ingredient

erlotinib

Inactive ingredients

lactose monohydrate

microcrystalline cellulose

sodium starch glycollate

magnesium stearate

isopropyl alcohol

The tablets have a film-coating

which contains:

Opadry 200 Optimised

Performance Coating

200F280000 White

Erlotinib Sandoz tablets contain

lactose and are gluten free.

Supplier

Erlotinib Sandoz is supplied in

Australia by:

Sandoz Pty Ltd

54 Waterloo Road

Macquarie Park NSW 2113

Tel: 1800 726 369

ERLOTINIB SANDOZ

Australian Registration Numbers

25 mg - AUST R 326623

100 mg - AUST R 326624

150 mg - AUST R 326622

This leaflet was prepared in

September 2020.

Read the complete document

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Page 1 of 23

AUSTRALIAN PRODUCT INFORMATION

ERLOTINIB SANDOZ

®

(ERLOTINIB (AS HYDROCHLORIDE))

1.

NAME OF THE MEDICINE

Erlotinib (as hydrochloride)

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Erlotinib Sandoz 25 mg film-coated tablet contains erlotinib hydrochloride equivalent to

25 mg of erlotinib.

Each Erlotinib Sandoz 100 mg film-coated tablet contains erlotinib hydrochloride equivalent

to 100 mg of erlotinib.

Each Erlotinib Sandoz 150 mg film-coated tablet contains erlotinib hydrochloride equivalent

to 150 mg of erlotinib.

Excipients with known effect:

lactose monohydrate.

For the full list of excipients, see Section 6.1 List of excipients.

3.

PHARMACEUTICAL FORM

Erlotinib Sandoz 25 mg film-coated tablets are white to yellowish, round biconvex, film-coated

tablets with ‘25’ engraved on one side. The diameter of the tablet is ~ 6.1 mm.

Erlotinib Sandoz 100 mg film-coated tablets are white to yellowish, round biconvex, film-

coated tablets with ‘100’ engraved on one side. The diameter of the tablet is ~ 8.9 mm.

Erlotinib Sandoz 150 mg film-coated tablets are white to yellowish, round biconvex, film-

coated tablets with ‘150’ engraved on one side. The diameter of the tablet is ~ 10.5 mm.

Not all strengths may be marketed in Australia.

4.

CLINICAL PARTICULARS

4.1.

T

HERAPEUTIC INDICATIONS

Non-small cell lung cancer

Erlotinib Sandoz is indicated for the first-line treatment of patients with advanced (Stage IIIB)

or metastatic (Stage IV) non-small cell lung cancer (NSCLC) with activating EGFR mutations.

Erlotinib Sandoz is indicated for maintenance therapy in patients with locally advanced or

metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations who have not

progressed on first-line chemotherapy.

Erlotinib Sandoz is also indicated for the treatment of patients with locally advanced or

metastatic non- small cell lung cancer after failure of prior chemotherapy.

Pancreatic cancer

Erlotinib Sandoz in combination with gemcitabine is indicated for the treatment of patients

with locally advanced, unresectable or metastatic pancreatic cancer.

200902-erlotinib sandoz-pi

Page 2 of 23

4.2.

D

OSE AND METHOD OF ADMINISTRATION

Non-Small Cell Lung Cancer

The recommended daily dose of Erlotinib Sandoz is 150 mg taken at least one hour before or

two hours after the ingestion

food. Treatment

should

continued

until

disease

progression

or unacceptable toxicity occurs. There is no evidence that treatment beyond

disease progression is beneficial.

When dose adjustment is necessary, reduce in 50 mg steps.

Pancreatic cancer

The recommended daily dose of Erlotinib Sandoz is 100 mg taken at least one hour before or

two hours after the ingestion of food, in combination with gemcitabine (see the gemcitabine

Product Information for the correct dosage of gemcitabine in pancreatic cancer). Treatment

should be continued until disease progression or unacceptable toxicity occurs.

Special Dosage Instructions

Concomitant use of CYP3A4 substrates and modulators may require dose adjustment (see

Sections 4.4 Special warnings and precautions for use and 4.5 Interactions with other medicines

and other forms of interactions).

Dosage adjustment in:

hepatic impairment

Erlotinib Sandoz treatment should be interrupted or discontinued if;

there is a doubling of total serum bilirubin and/or tripling of serum transaminases in

patients with baseline hepatic impairment

total serum bilirubin is > 3 x ULN and/or serum transaminases are > 5 x ULN in patients with

normal pre-treatment values (see Section 4.4 Special warnings and precautions for use)

paediatric population

The safety and efficacy of Erlotinib Sandoz has not been studied in patients under the age of

18 years.

4.3.

C

ONTRAINDICATIONS

Erlotinib Sandoz is contraindicated in patients with severe hypersensitivity to erlotinib or to

any of the excipients.

4.4.

S

PECIAL WARNINGS AND PRECAUTIONS FOR USE

EGFR Mutation Status

It is recommended that EGFR mutation testing should be performed prior to initiation of

erlotinib as first-line or maintenance therapy in patients with locally advanced or metastatic

NSCLC. A well-validated and robust test for activating EGFR mutations should be used.

200902-erlotinib sandoz-pi

Page 3 of 23

Combination with Chemotherapy

Randomised

controlled

trials

have

demonstrated

that

erlotinib

combined

with

doublet,

platinum-based cytotoxic chemotherapy in advanced NSCLC provides no added benefit over

cytotoxic chemotherapy alone.

Interstitial Lung Disease (ILD)

Cases of ILD-like events, including fatalities, have been reported uncommonly in patients

receiving erlotinib for treatment of NSCLC, pancreatic cancer or other advanced solid tumours.

In the pivotal Phase III study BR.21 in NSCLC, the incidence of serious ILD-like events (0.8%)

was the same in both the placebo and erlotinib groups. In a meta-analysis of NSCLC

randomised controlled clinical trials, the incidence of ILD-like events was 0.9% on erlotinib

compared to 0.4% in patients in the control arms.

In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like

events was 2.5% in the erlotinib plus gemcitabine group versus 0.4% in the placebo plus

gemcitabine-treated group. Some examples of reported diagnoses in patients suspected of

having

ILD-like

events

included

pneumonitis,

radiation

pneumonitis,

hypersensitivity

pneumonitis,

interstitial

pneumonia,

interstitial

lung

disease,

obliterative

bronchiolitis,

pulmonary fibrosis, Acute Respiratory Distress Syndrome, lung infiltration and alveolitis.

These ILD-like events started from a few days to several months after initiating erlotinib

therapy. Most of the cases were associated with confounding or contributing factors such as

concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease,

metastatic lung disease or pulmonary infections. A causal association of ILD-like events to

erlotinib therapy has not been established.

In patients who develop acute onset of new and/or progressive unexplained pulmonary

symptoms such as dyspnoea, cough and fever, erlotinib therapy should be interrupted pending

diagnostic evaluation. If ILD is diagnosed, erlotinib should be discontinued and appropriate

treatment initiated as necessary (see Section 4.8 Adverse effects (Undesirable effects)).

ECG Effects

In vitro

studies indicate that erlotinib blocks the hERG K

channel, producing 20% inhibition

at concentrations 1.6 – 8 times higher than the peak free erlotinib concentration in humans and

therefore has the potential to inhibit cardiac action potential repolarisation. The clinical

significance of these findings is unknown and adverse ECG effects have not been observed in

human studies to date.

Diarrhoea and Dehydration

Diarrhoea has occurred in patients on erlotinib and moderate or severe diarrhoea should be

treated with loperamide. In some cases, dose reduction may be necessary. In the event of severe

or persistent diarrhoea, nausea, anorexia or vomiting associated with dehydration, erlotinib

therapy

should

interrupted

appropriate

measures

should

taken

treat

dehydration.

Hypokalaemia, Renal Failure

There have been rare reports of hypokalaemia and renal failure (including fatalities). Some

reports of renal failure were secondary to severe dehydration due to diarrhoea, vomiting and/or

anorexia, while others were confounded by concomitant chemotherapy. In more severe or

200902-erlotinib sandoz-pi

Page 4 of 23

persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients

with aggravating risk factors (concomitant medications, symptoms or diseases or other

predisposing conditions including advanced age), erlotinib therapy should be interrupted and

appropriate measures should be taken to intensively rehydrate the patients intravenously. In

addition, renal function and serum electrolytes including potassium should be monitored in

patients at risk of dehydration.

Lactose Intolerance

Erlotinib tablets contain lactose and should not be administered to patients with rare hereditary

problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Hepatotoxicity, Hepatitis, Hepatic Failure

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate

aminotransferase (AST), bilirubin) have been observed infrequently. These were mainly mild

or moderate in severity, transient in nature or associated with liver metastases.

Rare cases of hepatic failure and hepatorenal syndrome (including fatalities) have been

reported during use of erlotinib. Confounding factors have included pre-existing liver disease

or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function

testing should be considered.

Erlotinib treatment should be interrupted or discontinued if changes in liver function are severe

(see Sections 4.2 Dose and method of administration and 4.4 Special warnings and precautions

for use).

Gastrointestinal Perforations

Patients receiving erlotinib are at an increased risk of developing gastrointestinal perforation,

which was observed uncommonly (including some cases with a fatal outcome). Patients

receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based

chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at

increased

risk.

Erlotinib

should

permanently

discontinued

patients

develop

gastrointestinal perforation (see Section 4.8 Adverse effects (Undesirable effects)).

Bullous and Exfoliative Skin Disorders

Bullous, blistering and exfoliative skin conditions have been reported, including very rare cases

suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases

were fatal (see Section 4.8 Adverse effects (Undesirable effects)). Erlotinib treatment should

be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliative

conditions.

Ocular Disorders

Very rare cases of corneal perforation or ulceration have been reported during use of erlotinib.

Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or

keratitis have been observed with erlotinib treatment which are also risk factors for corneal

perforation/ulceration. Erlotinib therapy should be interrupted or discontinued if patients

present with acute/worsening ocular disorders such as eye pain (see Section 4.8 Adverse effects

(Undesirable effects)).

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Page 5 of 23

Use in hepatic impairment

In view of the variability in pharmacokinetics, erlotinib should be used with caution in patients

with

hepatic

impairment

dose

tailored

individual

patients

(see

Section

Pharmacokinetic properties - Special Populations, Hepatic Impairment).

Patients with hepatic impairment are at increased risk of hepatic failure during treatment with

erlotinib. Therefore, close monitoring of hepatic function is recommended. Erlotinib treatment

should be interrupted or discontinued if changes in hepatic function are severe (see Sections 4.2

Dose and method of administration and 4.4 Special warnings and precautions for use).

The safety and efficacy of erlotinib have not been studied in patients with severe hepatic

impairment (total serum bilirubin > 3 x ULN). Use of erlotinib in patients with severe hepatic

impairment is not recommended.

Use in renal impairment

The safety and efficacy of erlotinib has not been studied in patients with renal impairment.

Use in the elderly

Of the total number of patients participating in the Phase III study BR. 21, 62% were less than

65 years of age and 38% of patients were aged 65 years or older. The survival benefit was

maintained across both age groups (see Section 5.1 Pharmacodynamic properties). No

meaningful differences in safety or pharmacokinetics were observed between younger and

older patients. Therefore, no dosage adjustments are recommended in elderly patients.

Paediatric use

The safety and efficacy of erlotinib has not been studied in patients under the age of 18 years.

Effects on laboratory tests

No data available.

4.5.

I

NTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS

Erlotinib is metabolised by the hepatic cytochromes in humans, primarily CYP3A4/CYP3A5

and to a lesser extent by CYP1A2 and the pulmonary isoform CYP1A1. Potential interactions

may occur with medicines that are metabolised by, or are inhibitors or inducers of, these

enzymes.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib

plasma concentrations. Inhibition of CYP3A4 metabolism by ketoconazole (200 mg orally

twice daily for 5 days) resulted in increased exposure to erlotinib (86% in median erlotinib

AUC) and a 69% increase in maximum concentration (C

) when compared to erlotinib alone.

When erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and

CYP1A2, erlotinib exposure [AUC] and C

increased by 39% and 17% respectively.

Therefore, caution should be used when administering erlotinib with potent CYP3A4 or

combined CYP3A4/CYP1A2 inhibitors such as ketoconazole, atazanavir, clarithromycin,

erythromycin,

indinavir,

itraconazole,

nefazodone,

nelfinavir,

ritonavir,

saquinavir,

telithromycin, troleandomycin and voriconazole. In these situations, the dose of erlotinib

should be reduced if toxicity is observed.

Potent inducers of CYP3A4 increase erlotinib metabolism and significantly decrease erlotinib

plasma concentrations. Induction of CYP3A4 metabolism by rifampicin (600 mg orally, 4

200902-erlotinib sandoz-pi

Page 6 of 23

times a day for 7 days) resulted in a 69% decrease in the median erlotinib AUC, following a

150 mg dose of erlotinib, as compared to erlotinib alone.

In another study, pre-treatment and co-administration of rifampicin with a single 450 mg dose

of erlotinib resulted in a decreased mean erlotinib exposure [AUC], which was 57.5% of a

single 150 mg erlotinib dose in the absence of rifampicin treatment. Therefore, caution should

be used when administering erlotinib with potent CYP3A4 inducers such as rifampicin,

rifabutin, rifapentin, phenytoin, carbamazepine, phenobarbital and St. John’s Wort. Alternative

treatments lacking potent CYP3A4 inducing activity should be considered when possible. For

patients who require concomitant treatment with erlotinib and a potent CYP3A4 inducer such

as rifampicin, an increase in dose to 300 mg should be considered while their safety is closely

monitored and if well tolerated for more than 2 weeks, a further increase to 450 mg could be

considered with close safety monitoring. Higher doses have not been studied in this setting.

Pre-treatment or co-administration of erlotinib did not alter the clearance of the prototypical

CYP3A4 substrates midazolam and erythromycin. Significant interactions with the clearance

of other CYP3A4 substrates are therefore unlikely. Oral availability of midazolam did appear

to decrease by up to 24%, which was however not attributed to effects on CYP3A4 activity.

The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases.

Medicines that alter the pH of the upper gastrointestinal tract may alter the solubility of erlotinib

and hence its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump

inhibitor, decreased the erlotinib exposure [AUC] and C

by 46% and 61% respectively.

There was no change to T

or half-life. Concomitant administration of erlotinib with 300 mg

ranitidine, a H

-receptor antagonist, decreased

erlotinib

exposure [AUC] and C

by 33% and

54% respectively. Therefore, co-administration of erlotinib with medicines that reduce gastric

acid production should be avoided where possible. Increasing the dose of erlotinib is not likely

to compensate for loss of exposure. However, when erlotinib was dosed in a staggered manner

2 hours before or 10 hours after ranitidine 150 mg twice daily, erlotinib exposure [AUC] and

decreased by 15% and 17% respectively. If patients need to be treated with such

medicines, an H

-receptor antagonist such as ranitidine should be considered and used in a

staggered manner. Erlotinib must be taken at least 2 hours before or 10 hours after the H

receptor antagonist dosing.

International

Normalized

Ratio

(INR)

elevations

bleeding

events,

including

gastrointestinal

bleeding,

have

been

reported

clinical

studies,

some

associated

with

concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative

anticoagulants should be monitored regularly for changes in prothrombin time or INR.

The combination of erlotinib and a statin may increase the potential for statin-induced

myopathy, including rhabdomyolysis, which was observed rarely.

In a Phase Ib study, there were no significant effects of gemcitabine on the pharmacokinetics

erlotinib

were there significant effects of

erlotinib on

the pharmacokinetics of

gemcitabine.

The impact of smoking on erlotinib efficacy is not known, however, smokers should be advised

to stop smoking as cigarette smoking, which is known to induce CYP1A1 and CYP1A2, has

been shown to reduce erlotinib exposure by 50 – 60% (see Section 5.2 Pharmacokinetic

properties).

200902-erlotinib sandoz-pi

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4.6.

F

ERTILITY

,

PREGNANCY AND LACTATION

Effects on fertility

Erlotinib

impair

fertility in

male

rats

given

doses

that

result

plasma

drug

concentrations similar to that of humans. Erlotinib administered at 10 mg/kg/day (1.5 times the

clinical dose based on relative AUC) for 2 weeks prior to mating until day 7 of gestation

affected ovulation in female rats, resulting in a reduction in the number of corpora lutea.

Use in pregnancy

Category C

There are no adequate or well-controlled studies in pregnant women using erlotinib. Studies in

animals have shown some reproductive toxicity (see Section 5.3 Preclinical safety data). The

potential for humans is unknown.

Women of childbearing potential must be advised to avoid pregnancy while on erlotinib.

Adequate contraceptive methods should be used during therapy and for at least 2 weeks after

completing therapy. Treatment should only be continued in pregnant women if the potential

benefit to the mother outweighs the risk to the foetus.

Use in lactation

It is not known whether erlotinib is excreted in human milk. No studies have been conducted

to assess the impact of erlotinib on milk production or its presence in breast milk. As the

potential for harm to the nursing infant is unknown, mothers should be advised against

breastfeeding while receiving erlotinib and for at least 2 weeks after the final dose.

4.7.

E

FFECTS ON ABILITY TO DRIVE AND USE MACHINES

The effects of this medicine on a person's ability to drive and use machines were not assessed

as part of its registration.

4.8.

A

DVERSE EFFECTS

(U

NDESIRABLE EFFECTS

)

Safety evaluation of erlotinib is based on the data from more than 1500 patients treated with at

least one 150 mg dose of erlotinib monotherapy, and more than 300 patients who received

erlotinib 100 mg or 150 mg in combination with gemcitabine.

The incidence of adverse reactions reported with erlotinib alone or in combination with

chemotherapy are summarised in the tables below and are based on data from clinical trials.

The listed adverse reactions were those reported in at least 10% (in the erlotinib group) of

patients and occurred more frequently (≥ 3%) in patients treated with erlotinib than in the

comparator arm.

Erlotinib monotherapy

The adverse reactions listed in Table 1 are based on data from the pivotal study BR.21

conducted in 731 patients with locally advanced or metastatic NSCLC after failure of at least

one prior chemotherapy regimen. Patients were randomised 2:1 to receive erlotinib 150 mg or

placebo, taken orally once daily until disease progression or unacceptable toxicity.

The most frequent adverse reactions were rash and diarrhoea (any Grade, 75% and 54%

respectively), most were Grade 1 – 2 in severity and manageable without intervention. Grade

3 or Grade 4 rash and diarrhoea occurred in 9% and 6% respectively in erlotinib-treated patients

200902-erlotinib sandoz-pi

Page 8 of 23

and each resulted in study discontinuation in 1% of patients. Rash and diarrhoea diminished

following discontinuation of erlotinib. Dose reduction for rash and diarrhoea was needed in

6% and 1% of patients respectively. In study BR.21, the median time to onset of rash was 8

days and the median time to onset of diarrhoea was 12 days.

Table 1. Adverse reactions occuring more frequently (≥ 3%) in erlotinib-treated group than in the

placebo group and in ≥ 10% of patients in the erlotinib group in study BR.21

Erlotinib

n = 485

Placebo

n = 242

NCI-CTC Grade

Any Grade

3

4

Any

Grade

3

4

MedDRA Preferred Term

%

%

%

%

%

%

Total patients with any AE

Skin and subcutaneous tissue disorders

Rash

<1

Pruritus

<1

Dry skin

Gastrointestinal disorders

Diarrhoea

<1

<1

Nausea

Vomiting

<1

Stomatitis

<1

Abdominal pain

<1

<1

General disorders and administration site conditions

Fatigue

Metabolism and nutrition disorders

Anorexia

<1

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cough

Infections and infestations*

Infection

Eye disorders

Conjunctivitis

<1

<1

Keratoconjunctivitis sicca

*

severe infections, with or without neutropenia, have included pneumonia, sepsis and cellulitis.

In two other double-blind, randomised, placebo-controlled Phase III studies (BO18192 and

BO25460) conducted in a total of 1532 patients with advanced, recurrent or metastatic NSCLC

following first-line standard platinum-based chemotherapy, no new safety signals were

identified in the safety analysis population.

The most frequent adverse reaction seen in patients treated with erlotinib in studies BO18192

and BO25460 were rash and diarrhoea (see Table 2). No Grade 4 rash or diarrhoea was

200902-erlotinib sandoz-pi

Page 9 of 23

observed in either study. Rash and diarrhoea resulted in discontinuation of erlotinib in 1% and

< 1% of patients respectively, in Study BO18192, while no patient discontinued for rash or

diarrhoea in BO25460. Dose modifications (interruptions or reductions) for rash and diarrhoea

were needed in 8.3% and 3% of patients, respectively, in Study BO18192 and 5.6% and 2.8%

of patients, respectively, in Study BO25460.

Table 2. ADR tablet for the most frequent ADRs in BO18192 (SATURN) and BO25460 (IUNO) studies

BO18192 (SATURN)*

BO25460 (IUNO)*

MedDRA

Preferred Term

Erlotinib

n=433

Placebo

n=445

Erlotinib

n=322

Placebo

n=319

Rash, all grades

49.2

39.4

10.0

Grade 3

Diarrhoea, all grades

20.3

24.2

Grade 3

*Safety analysis population

In the open-label, randomised phase III study ML 20650, conducted in 154 patients, the safety

of erlotinib for first-line treatment of NSCLC patients with EGFR activating mutations was

assessed in 75 patients; no new safety signals were observed in these patients.

The most frequent adverse reactions seen in patients treated with erlotinib in study ML 20650

were rash and diarrhoea (any Grade 80% and 57%, respectively), most were Grade 1 - 2 in

severity and manageable without intervention. Grade 3 rash and diarrhoea occurred in 9% and

4% of patients, respectively. No Grade 4 rash or diarrhoea was observed. Both rash and

diarrhoea resulted in discontinuation of erlotinib in 1% of patients. Dose modifications

(interruptions or reductions) for rash and diarrhoea were needed in 11% and 7% of patients,

respectively.

Erlotinib in combination with chemotherapy

The adverse reactions listed in Table 3 are based on the erlotinib arm data from a controlled

clinical trial (PA.3) where 259 patients with pancreatic cancer received erlotinib 100 mg plus

gemcitabine compared to 256 patients in the placebo plus gemcitabine arm.

The most frequent adverse reactions in study PA.3 in pancreatic cancer patients receiving

erlotinib 100 mg plus gemcitabine were fatigue (73%), rash (69%) and diarrhoea (48%). In the

erlotinib plus gemcitabine arm, Grade 3 or Grade 4 rash and diarrhoea were reported in 5% of

patients. The median time to onset of rash and diarrhoea was 10 days and 15 days respectively.

Rash and diarrhoea each resulted in dose reductions in 2% of patients and resulted in study

discontinuation in up to 1% of patients receiving erlotinib plus gemcitabine.

The erlotinib 150 mg plus gemcitabine cohort (23 patients) was associated with a higher rate of

certain class-specific adverse reactions including rash and required more frequent dose

reduction or interruption.

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Page 10 of 23

Table 3. Adverse reactions occurring ≥ 10% and more frequently (≥ 3%) in erlotinib 100 mg plus

gemcitabine-treated patients than in the placebo plus gemcitabine group in Study PA.3

Erlotinib plus gemcitabine

n = 259

Placebo plus gemcitabine

n = 256

NCI-CTC Grade

Any

Grade

3

4

Any

Grade

3

4

MedDRA Preferred Term

%

%

%

%

%

%

Total patients with any AE

Skin and subcutaneous tissue disorders

Rash

Alopecia

Gastrointestinal disorders

Diarrhoea

<1

Stomatitis

<1

Dyspepsia

<1

<1

Flatulence

<1

Metabolism and nutrition disorders

Weight decreased

<1

General disorders and administration site

conditions

Pyrexia

Fatigue

Rigors

Infections and infestations

Infection*

<1

<1

Psychiatric disorders

Depression

<1

Respiratory, thoracic and mediastinal

disorders

Cough

Nervous system disorders

Headache

<1

Neuropathy

<1

<1

*

severe infections, with or without neutropenia, have included pneumonia, sepsis and cellulitis.

Further information on adverse reactions of special interest:

The following adverse reactions have been observed in patients who received erlotinib

monotherapy or erlotinib 100 mg and 150 mg in combination with gemcitabine.

The following terms are used to rank the adverse reactions by frequency:

very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100);

rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000) including isolated reports.

Very common adverse reactions are presented in Tables 1, 2 and 3, adverse events in other

frequency categories are summarised below:

200902-erlotinib sandoz-pi

Page 11 of 23

Gastrointestinal disorders

Gastrointestinal perforations have been reported uncommonly (in less than 1% of patients) with

erlotinib treatment, in some cases with a fatal outcome (see Section 4.4 Special warnings and

precautions

use).

Cases

gastrointestinal

bleeding

have

been

reported

commonly

(including some fatalities), some associated with concomitant warfarin administration (see

Sections 4.4 Special warnings and precautions for use and 4.5 Interactions with other medicines

and other forms of interactions) and some with concomitant NSAID administration.

Hepatobiliary disorders

Liver function test abnormalities (including elevated alanine aminotransferase [ALT], aspartate

aminotransferase [AST], bilirubin) have been observed commonly in clinical trials of erlotinib.

In study PA.3, these occurred very commonly. They were mainly mild or moderate in severity,

transient in nature or associated with liver metastases. Rare cases of hepatic failure and

hepatorenal syndrome (including fatalities) have been reported during use of erlotinib.

Confounding factors have included pre-existing liver disease or concomitant hepatotoxic

medications. (see Section 4.4 Special warnings and precautions for use).

Eye disorders

Corneal ulcerations or perforations have been reported very rarely in patients receiving erlotinib

treatment (see Section 4.4 Special warnings and precautions for use).

Keratitis and conjunctivitis has been reported commonly with erlotinib. Abnormal eyelash

growth including: in-growing eyelashes, excessive growth and thickening of the eyelashes have

been reported (see Section 4.4 Special warnings and precautions for use).

Respiratory, thoracic and mediastinal disorders

There have been uncommon reports of serious interstitial lung disease, including fatalities, in

patients receiving erlotinib for treatment of NSCLC and other advanced solid tumours.

Cases of epistaxis have also been reported commonly in both the NSCLC and the pancreatic

cancer trials.

Skin and subcutaneous tissue disorders

Rash has been reported very commonly in patients receiving erlotinib and in general, manifests

as a mild or moderate erythematous and papulopustular rash, which may occur or worsen in

sun exposed areas. For patients who are exposed to sun, protective clothing and/or use of

sunscreen may be advisable. Acne, dermatitis acneiform and folliculitis have been observed

commonly, most of these events were mild or moderate and non-serious. Skin fissures, mostly

non-serious, were reported commonly and in the majority of cases were associated with rash

and dry skin. Other mild skin reactions such as hyperpigmentation have been observed

uncommonly (in less than 1% of patients).

Bullous, blistering and exfoliative skin conditions have been reported, including very rare cases

suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases

were fatal (see Section 4.4 Special warnings and precautions for use). Hair and nail changes,

mostly non-serious, were reported in clinical trials, e.g. paronychia was reported commonly

and hirsutism, eyelash/eyebrow changes and brittle and loose nails were reported uncommonly.

200902-erlotinib sandoz-pi

Page 12 of 23

Cardiovascular disorders

In the pivotal pancreatic cancer trial there was an excess of myocardial infarction/ischaemia

(2.3% vs 1.2%) and cerebrovascular accidents (2.3% vs 0%) in the erlotinib/gemcitabine group

compared to the placebo/gemcitabine group.

Post-Marketing Experience

Skin and subcutaneous tissue disorders

Hair and nail changes, mostly non-serious, have been reported uncommonly from post-

marketing surveillance, e.g. hirsutism, eyelash/eyebrow changes, paronychia and brittle and

loose nails.

Cases of uveitis have been reported during post-marketing surveillance.

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important.

It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-

problems.

4.9.

O

VERDOSE

Single oral doses of erlotinib up to 1000 mg in healthy subjects and up to 1600 mg given as a

single dose once weekly in cancer patients have been tolerated. Repeated twice daily doses of

200 mg in healthy subjects were poorly tolerated after only a few days of dosing. Based on the

data from these studies, severe adverse events such as diarrhoea, rash and possibly liver

transaminase elevation may occur above the recommended dose of 150 mg. In case of

suspected

overdose,

erlotinib

should

withheld

symptomatic

treatment

initiated.

Treatment should consist of general supportive measures.

For information on the management of overdose, contact the Poisons Information Centre on

13 11 26 (Australia).

5.

PHARMACOLOGICAL PROPERTIES

5.1.

P

HARMACODYNAMIC PROPERTIES

Pharmacotherapeutic

group:

antineoplastic

agent

protein

kinase

inhibitor,

code:

L01XE03

Mechanism of action

Erlotinib potently inhibits the intracellular phosphorylation of HER1/EGFR tyrosine kinase

with nanomolar potency; HER1/EGFR is expressed on the cell surface of normal cells and

cancer cells of epithelial origin. However, the mechanism of antitumour action of erlotinib is

not fully characterised. Erlotinib has been demonstrated to inhibit proliferation and/or induce

apoptosis in human cancer cell lines

in vitro

and to inhibit the growth of a variety of human

tumour xenografts in nude mice. Specificity of inhibition with regard to other tyrosine kinase

receptors has not been fully characterised.

200902-erlotinib sandoz-pi

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Clinical trials

Non-Small Cell Lung Cancer (NSCLC) – Erlotinib monotherapy

First-line therapy for patients with Epidermal Growth Factor Receptor (EGFR) activating

mutations

The efficacy of erlotinib in first-line treatment of patients with EGFR activating mutations in

NSCLC was demonstrated in a phase III, randomised, open-label trial (ML20650, EURTAC).

This study was conducted in Caucasian patients with metastatic or locally advanced NSCLC

(stage IIIB and IV) who have not received previous chemotherapy or any systemic antitumour

therapy for their advanced disease and who present mutations in the tyrosine kinase domain of

the EGFR (exon 19 deletion or exon 21 mutation). Patients were randomised 1:1 to receive

erlotinib 150 mg orally once daily or platinum based doublet chemotherapy.

The primary endpoint of investigator assessed progression free survival (PFS), was determined

at a pre-planned interim analysis (n=153, hazard ratio (HR) = 0.42, 95 % CI, 0.27 to 0.64;

p<0.0001 for the erlotinib group (n=77) relative to the chemotherapy group (n=76)). A 58%

reduction in the risk of disease progression or death was observed. In the erlotinib versus

chemotherapy arms, median PFS was 9.4 and 5.2 months, respectively. The median duration

of follow-up was 14.3 months for erlotinib patients and 10.7 months for chemotherapy patients.

Objective response rate (ORR) was 54.5 % and 10.5%, respectively. PFS results were

confirmed by an independent review of the scans, median PFS was 10.4 months in the erlotinib

group compared with 5.4 months in the chemotherapy group (HR=0.47, 95 % CI, 0.28 to 0.78;

p=0.003). The overall survival (OS) data were immature at the time of interim analysis (HR=

0.80, 95 % CI, 0.47 to 1.37, p=0.4170).

At an updated analysis with 62% of OS maturity, OS HR was 0.93 (95% CI, 0.64 to 1.36, p =

0.7149). A high crossover was observed with 82% of the patients in the chemotherapy arm

receiving subsequent therapy with an EGFR tyrosine kinase inhibitor and all but 2 of those

patients had subsequent erlotinib. In the updated analysis, PFS results remained consistent with

the interim analysis results. Median PFS assessed by the investigators was 10.4 and 5.1 months

in the erlotinib and chemotherapy arms respectively (HR = 0.34, 95% CI, 0.23 to 0.49,

p<0.0001).

First-line maintenance therapy

The efficacy and safety of erlotinib as first-line maintenance therapy of NSCLC was

demonstrated in a randomised, double-blind, placebo-controlled trial BO18192 (SATURN).

This study was conducted in 889 patients with locally advanced or metastatic NSCLC who did

progress

during

cycles

platinum-based

doublet

chemotherapy.

Patients

were

randomised 1:1 to receive erlotinib 150 mg or placebo orally once daily. The co-primary end-

point of the study was progression free survival (PFS) in all patients and in patients with an

EGFR IHC positive tumour. Baseline demographic and disease characteristics were well

balanced between the two treatment arms.

In this study BO18192 (SATURN), the overall population showed a benefit for the primary

PFS end-point (HR= 0.71 p<0.0001) and the secondary OS end-point (HR=0.81 p=0.0088).

However the largest benefit was observed in a predefined exploratory analysis in patients with

EGFR activating mutations (n=49) demonstrating a substantial PFS benefit (HR=0.10, 95%

CI, 0.04 to 0.25; p<0.0001) and an overall survival HR of 0.83 (95% CI, 0.34 to 2.02; p<0.

6810). 67% of placebo patients in the EGFR mutation positive subgroup received second or

further line treatment with EGFR-TKIs. In patients with EGFR wild type tumours (n=388), the

200902-erlotinib sandoz-pi

Page 14 of 23

PFS HR was 0.78 (95% CI, 0.63 to 0.96; p=0.0185) and the overall survival HR was 0.77 (95%

CI, 0.61 to 0.97; p=0.0243). The study was not powered to show statistically significant

differences for OS in the EGFR wild type and EGFR mutation positive subgroups.

The BO25460 (IUNO) study was conducted in 643 patients with advanced NSCLC whose

tumours did not harbour an EGFR-activating mutation (exon 19 deletion or exon 21 L858R

mutation) and who had not experienced disease progression after four cycles of platinum-based

chemotherapy.

The objective of the study was to compare the overall survival of first line maintenance therapy

with erlotinib versus erlotinib administered at the time of disease progression. The study did

not meet its primary endpoint. OS of erlotinib in first line maintenance was not superior to

erlotinib as second line treatment in patients whose tumour did not harbour an EGFR-activating

mutation (HR=1.02, 95% CI, 0.85 to 1.22, p=0.82). The secondary endpoint of PFS showed no

difference between erlotinib and placebo in maintenance treatment (HR=0.94, 95% CI, 0.80 to

1.11; p=0.48).

Based on the data from the BO25460 (IUNO) study, erlotinib use is not recommended for first-

line maintenance treatment in patients without an EGFR activating mutation.

Second-line and third-line therapy

The efficacy and safety of erlotinib in second and third line therapy of NSCLC was

demonstrated in a randomised, double-blind, placebo-controlled trial (Study BR.21). This

study was conducted in 17 countries, in 731 patients with locally advanced or metastatic

NSCLC after failure of at least one chemotherapy regimen. Patients, following disease

progression, were randomised 2:1 to receive erlotinib 150 mg (

n

= 488) or placebo (

n

= 243)

orally once daily. Study endpoints included overall survival, time to deterioration of lung

cancer-related symptoms (cough, dyspnoea and pain), response rate, duration of response,

progression-free survival (PFS) and safety. The primary end-point was survival.

Patients were not selected for HER1/EGFR status, gender, race, smoking history or histologic

classification. Demographic characteristics were well balanced between the two treatment

groups (see Table 4). Approximately two-thirds of the patients were male and approximately

one-third had a baseline ECOG performance status (PS) of 2 and 9% had a baseline ECOG PS

of 3. Ninety-three percent and 92% of all patients in the erlotinib and placebo groups

respectively, had received a prior platinum-containing regimen and 36% and 37% of all

patients respectively, had received a prior taxane therapy. Fifty percent of the patients had

received only one prior regimen of chemotherapy.

Table 4. Study BR.21 – Demographic and disease characteristics

Characteristics

Erlotinib

n = 488

Placebo

n = 243

n

(%)

n

(%)

Gender

Female

(35)

(34)

Male

(65)

(66)

Age (years)

< 65

(61)

(63)

≥ 65

(39)

(37)

ECOG Performance Status

(13)

(14)

(52)

(54)

200902-erlotinib sandoz-pi

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Characteristics

Erlotinib

n = 488

Placebo

n = 243

n

(%)

n

(%)

(26)

(23)

Smoking History

Never smoked

(21)

(17)

Current or Ex-smoker

(73)

(77)

Unknown

Histological classification

Adenocarcinoma

(50)

(49)

Squamous

(30)

(32)

Undifferentiated large cell

Mixed non-small cell

(<1)

Other

Number of prior regimens

(50)

(50)

(49)

(49)

Survival was evaluated in the intent-to-treat population. The median overall survival improved

by 42.5% and was 6.7 months in the erlotinib group compared with 4.7 months in the placebo

group (see Figure 1). The primary survival analysis was adjusted for the stratification factors

as reported at the time of randomisation (ECOG PS, best response to prior therapy, number of

prior regimens and exposure to prior platinum) and HER1/EGFR status. In this primary

analysis, the adjusted HR for death in the erlotinib group relative to the placebo group was 0.73

(95% CI: 0.60 – 0.87;

p

= 0.001). The percent of patients alive at 12 months was 31.2% and

21.5%, for the erlotinib and placebo groups respectively.

Figure 1. Kaplan-Meier curve for overall survival of patients by treatment group in Study BR.21

200902-erlotinib sandoz-pi

Page 16 of 23

The robustness of the overall survival result was examined in exploratory univariate analyses

of a number of patient subsets formed according to stratification factors. The survival benefit

with erlotinib treatment was seen across patient subsets including prior exposure to taxanes,

smoking history, gender, age, histology, prior weight loss, time between initial diagnosis and

randomisation and geographic location. The HR in the erlotinib group relative to the placebo

group were less than 1.0, suggesting that the survival benefit from erlotinib was robust across

subsets. Of note, the survival benefit of erlotinib was comparable in patients with a baseline

ECOG PS of 2 – 3 (HR = 0.77) or a PS of 0 – 1 (HR = 0.73) and patients who had received one

chemotherapy regimen (HR = 0.76) or two or more regimens (HR = 0.76).

A survival benefit of erlotinib was also observed in patients who did not achieve an objective

tumour response (by RECIST). This was evidenced by a HR for death of 0.82 among patients

whose best response was stable disease or progressive disease.

Summarised in Table 5 are the results for study BR.21, including survival, time to deterioration

of lung cancer-related symptoms and progression-free survival.

Table 5. Study BR.21 – Efficacy results

Erlotinib n = 488

Placebo

n = 243

p-value

Median survival

6.7 months

4.7 months

Difference between survival curves

0.001

Hazard Ratio

a

, mortality

0.73

0.001

(erlotinib: placebo)

95% CI

0.60 - 0.87

Median time to deterioration in cough

c

6.4 months

3.6 months

0.041

Median time to deterioration in dyspnoea

c

4.6 months

2.8 months

0.031

Median time to deterioration in pain

c

2.8 months

1.8 months

0.040

Median progression-free survival

2.2 months

1.8 months

<0.001

adjusted for stratification factors and HER1/EGFR status; a value less than 1.00 favours erlotinib (primary

analysis)

p-value adjusted for multiple testing

from the EORTC QLQ-C30 and QLQ-LC13 quality of life questionnaires

Symptom deterioration was measured using the EORTC QLQ-C30 and QLQ-LC13 quality of

life questionnaires. Baseline scores of cough, dyspnoea and pain were similar in the two

treatment groups. Erlotinib resulted in symptom benefits by significantly prolonging time to

deterioration in cough (HR = 0.75), dyspnoea (HR = 0.72) and pain (HR = 0.77) versus placebo.

These symptom benefits were not due to an increased use of palliative radiotherapy or

concomitant medications in the erlotinib group.

The median PFS was 2.2 months in the erlotinib group compared with 1.8 months in the placebo

group. The HR for progression, adjusted for stratification factors and HER1/EGFR status, was

0.61 (95% CI: 0.51 – 0.73;

p

< 0.001). The percent of PFS at 6 months was 24.5% and 9.3%

respectively, for the erlotinib and placebo groups.

The objective response rate by RECIST in the erlotinib group was 8.9% (95% CI: 6.4 – 12.0).

The median duration of response was 7.8 months, ranging from 2.2 months – 13.2+ months.

Two responses (0.9%, 95% CI: 0.1 – 3.4) were reported in the placebo group. The proportion

of patients who experienced complete response, partial response or stable disease was 44.0%

and 27.5% respectively, for the erlotinib and placebo groups (

p

= 0.004).

200902-erlotinib sandoz-pi

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In a double-blind, randomized phase III study (MO22162, CURRENTS) comparing two doses

of erlotinib (300 mg vs 150 mg) in current smokers (mean of 38 pack years) with locally

advanced or metastatic NSCLC in the second-line setting after failure on chemotherapy, the

300 mg dose of erlotinib demonstrated no PFS benefit over the recommended dose (7.00 vs

6.86 weeks, respectively). Patients in this study were not selected based on EGFR mutation

status.

Pancreatic cancer – Erlotinib in combination with gemcitabine

The efficacy and safety of erlotinib in combination with gemcitabine as a first line treatment

was assessed in a randomised, double blind, placebo-controlled trial in 569 patients with locally

advanced, unresectable or metastatic pancreatic cancer (Study PA.3). Patients were randomised

1:1 to receive erlotinib (100 mg or 150 mg) or placebo once daily on a continuous schedule

plus gemcitabine IV (1000 mg/m

, Cycle 1 - days 1, 8, 15, 22, 29, 36 and 43 of an 8-week cycle;

Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4-week cycle (approved dose and

schedule for pancreatic cancer according to gemcitabine product information). Erlotinib or

placebo was taken orally once daily until disease progression or unacceptable toxicity. Study

end points included overall survival, response rate and progression-free survival (PFS).

Duration of response was also examined. The primary endpoint was survival. A total of 285

patients were randomised to receive gemcitabine plus erlotinib (261 patients in the 100 mg

cohort and 24 patients in the 150 mg cohort) and 284 patients were randomised to receive

gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg

cohort). Too few observations were made for the 150 mg cohort to draw conclusions.

Baseline demographic and disease characteristics of the patients were similar between the 2

treatment groups except for a slightly larger proportion of females in the 100 mg erlotinib plus

gemcitabine arm (51%) compared with the placebo plus gemcitabine arm (44%). The median

time from initial diagnosis to randomisation was approximately 1.0 month. Approximately half

of the patients had a baseline ECOG performance status (PS) of 1 and 17% had a baseline ECOG

PS of 2. Most patients presented with metastatic disease at study entry as the initial

manifestation of pancreatic cancer (77% in the erlotinib arm, 76% in the placebo arm).

Survival was evaluated in the intent-to-treat population based on follow-up survival data

including 551 deaths. Results are presented for the 100 mg dose cohort (504 deaths) in Figure

2. The adjusted HR for death in the erlotinib group relative to the placebo group was 0.82 (95%

CI: 0.69 – 0.98;

p

= 0.028). The percentage of patients alive at 12 months was 23.8% in the

erlotinib group compared to 19.4% in the placebo group. The median overall survival was 6.4

months in the erlotinib group compared with 6 months in the placebo group.

200902-erlotinib sandoz-pi

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Figure 2. Kaplan-Meier curve for overall survival of patients in erlotinib 100 mg dose cohort by

treatment group in Study PA.3

Table 6. Study PA.3 – Efficacy results

Erlotinib 100 mg plus

gemcitabine

(n = 261)

Placebo plus

gemcitabine

(n = 260)

p-value

Median survival

6.4 months

6 months

Hazard ratio, mortality

(Erlotinib:placebo)

(95% CI)

0.82

(0.69 – 0.98)

0.028

% patients alive at 12 months

23.8

19.4

The median PFS was 3.81 months (16.5 weeks) in the erlotinib group (95% CI; 3.58 – 4.93)

compared with 3.55 months (15.2 weeks) in the placebo group (95% CI; 3.29 – 3.75;

p

= 0.006).

The median duration of response was 5.5 months, ranging from 0.85 months – 12.8+ months.

The objective response rate (complete response and partial response) was 8.6% in the erlotinib

group and 7.9% in the placebo group. The proportion of patients who experienced complete

response, partial response or stable disease was 59% and 49.4% respectively, for the erlotinib

and placebo groups (

p

= 0.036).

5.2.

P

HARMACOKINETIC PROPERTIES

Absorption

Oral erlotinib is well absorbed and has an extended absorption phase, with mean peak plasma

levels occurring at approximately 4 hours after oral dosing. A study in normal healthy

volunteers provided an estimate of bioavailability of 59%. The exposure after an oral dose may

be increased by food.

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Following absorption, erlotinib is highly bound in blood, with approximately 95% bound to

blood components, primarily to plasma proteins (i.e. albumin and alpha-1 acid glycoprotein

[AAG]).

Distribution

Erlotinib has a mean apparent volume of distribution of 232 L and distributes into tumour tissue

of humans. In a study of 4 patients (3 with non-small cell lung cancer [NSCLC] and 1 with

laryngeal cancer) receiving 150 mg daily oral doses of erlotinib, tumour samples from surgical

excisions on day 9 of treatment revealed tumour concentrations of erlotinib that averaged 1 185

ng/g of tissue. This corresponded to an overall average of 63% of the steady state observed

peak plasma concentrations. The primary active metabolites were present in tumours at

concentrations averaging 160 ng/g tissue, which corresponded to an overall average of 113%

of the observed steady state peak plasma concentrations. Tissue distribution studies using

whole body autoradiography following oral administration of [

C] labelled erlotinib in

athymic nude mice with HN5 (head and neck carcinoma) tumour xenografts have shown rapid

and extensive tissue distribution with maximum concentrations of radiolabeled drug in tumours

(approximately 73% of that in plasma) and most other tissues observed to coincide with the

peak plasma concentration.

Metabolism

Erlotinib is metabolised by the hepatic cytochromes in humans, primarily CYP3A4/ CYP3A5

and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1

in lung and CYP1B1 in tumour tissue potentially contribute to the metabolic clearance of

erlotinib.

In vitro

studies indicate approximately 80 – 95% of erlotinib metabolism is by the

CYP3A4 enzyme. There are 3 main metabolic pathways identified: 1) O-demethylation of

either side chain or both, followed by oxidation to the carboxylic acids; 2) oxidation of the

acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and 3) aromatic

hydroxylation of the phenyl-acetylene moiety. The primary metabolites of erlotinib produced

by O-demethylation of either side chain have comparable potency to erlotinib in preclinical

in

vitro

assays. They are present in plasma at levels that are < 10% of erlotinib and display similar

pharmacokinetics to erlotinib. The metabolites and trace amounts of erlotinib are excreted

predominantly via the faeces (> 90%), with renal elimination accounting for only a small

amount of an oral dose.

Excretion

A population pharmacokinetic analysis in 591 patients receiving single agent erlotinib (252

patients from Phase II studies A248-101, A248-1003, A248-1007 and OSI2288g; 339 patients

from Phase III study BR.21) show a mean apparent clearance of 4.47 L/hour with a median

half-life of 36.2 hours. Therefore, the time to reach steady state plasma concentration would be

expected to occur in approximately 7 – 8 days. No significant relationships between predicted

apparent clearance and patient age, body weight, gender and ethnicity were observed.

Patient factors, which correlate with erlotinib pharmacokinetics, are serum total bilirubin, AAG

and current smoking. Increased serum concentrations of total bilirubin and AAG were

associated with a slower rate of erlotinib clearance, however, smokers had a higher rate of

erlotinib clearance.

A second population pharmacokinetic analysis was conducted incorporating erlotinib data from

pancreatic

cancer

patients

received

erlotinib

plus

gemcitabine.

This

analysis

demonstrated that covariates affecting erlotinib clearance in patients from the pancreatic study

200902-erlotinib sandoz-pi

Page 20 of 23

were very similar to those seen in the prior single-agent pharmacokinetic analysis. No new

covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib

plasma clearance.

Following a 150 mg oral dose of erlotinib (591 patients – see above), at steady state, the median

time to reach maximum plasma concentration is approximately 4 hours with median maximum

plasma concentration achieved of 1995 ng/mL. Prior to the next dose at 24 hours, the median

minimum plasma concentration is 1238 ng/mL. Median AUC achieved during the dosing

interval at steady state is 41.3

g.h/mL.

Pharmacokinetics in Special Populations

Hepatic impairment

Erlotinib is primarily cleared by the liver. Erlotinib exposure was similar in patients with

moderately impaired hepatic function (Child-Pugh score 7 – 9) compared with patients with

adequate hepatic function.

The pharmacokinetics of erlotinib and its o-demethylated metabolites OSI-420 and OSI-413

were assessed in 36 patients with advanced solid tumours after a single 150 mg oral dose.

Twenty-one patients had adequate hepatic function (total serum bilirubin ≤ upper limit of

normal (ULN) and AST/AST ≤ 1.5 x ULN) and 15 had moderate hepatic impairment (Child-

Pugh score 7 – 9).

Erlotinib and metabolite exposures were similar in the two groups, with geometric mean AUCs

of 29 and 27 μg.h/mL for erlotinib in adequate and impaired hepatic function respectively and

2.0 and 2.4 μg.h/mL for metabolites respectively. However, the confidence intervals of the

ratios of the AUCs were wide, so it could not be concluded that exposures were equivalent.

The C

of erlotinib was significantly lower in moderate hepatic impaired patients compared

with those with adequate hepatic function consistent with delayed T

. The differences in

and T

are not clinically significant.

Renal impairment

Erlotinib and its metabolites are not significantly excreted by the kidneys (less than 9% of a

single dose is excreted in the urine). No clinical studies have been conducted in patients with

compromised renal function.

Smokers

A pharmacokinetic study in healthy non-smoking subjects and healthy subjects who currently

smoke has shown that cigarette smoking leads to increased clearance of, and decreased

exposure to, erlotinib. After a single 150 mg dose of erlotinib, the AUC

0-infinity

in smokers was

about 1/3 of that in never/former smokers (

n

= 16 in each of the smoker and never/former

smoker arms). This reduced exposure in smokers is presumably due to induction of CYP1A1

in the lungs and CYP1A2 in the liver.

In the pivotal Phase III NSCLC trial (see Section 5.1 Pharmacodynamic properties – Clinical

trials), smokers achieved a median erlotinib steady state trough plasma concentration of 0.65

μg/mL (

n

= 16) which was approximately 2-fold less than the former smokers or patients who

had never smoked (1.28 μg/mL,

n

= 108). This effect was accompanied by a 24% increase in

apparent erlotinib plasma clearance.

200902-erlotinib sandoz-pi

Page 21 of 23

In a Phase I dose escalation study in NSCLC patients who smoked, pharmacokinetic analyses

at steady state indicated a dose proportional increase in erlotinib exposure when the erlotinib

dose was increased from 150 mg to the maximum tolerated dose of 300 mg. Median steady

state trough plasma concentration at a 300 mg dose in smokers in this study was 1.22 μg/mL

n

= 17) compared with 0.38 μg/mL (

n

= 15) at 150 mg

.

In a double-blind, randomized phase

III study (MO22162, CURRENTS) comparing two doses of erlotinib (300 mg vs 150 mg) in

current smokers with locally advanced or metastatic NSCLC, a 300 mg dose did not show

improved efficacy in second line treatment after failure of chemotherapy compared to the

recommended 150 mg dose in patients who continue to smoke cigarettes (see Section 5.1

Pharmacodynamic properties – Clinical trials).

5.3.

P

RECLINICAL SAFETY DATA

Genotoxicity

Erlotinib has been tested for genotoxicity in a series of

in vitro

assays (bacterial mutation, human

lymphocyte chromosome aberration and mammalian cell mutation) and an

in vivo

mouse

micronucleus test. Under the conditions of these assays, erlotinib did not cause genetic damage.

Carcinogenicity

In 2 year carcinogenicity studies, mice given daily oral doses of erlotinib at up to 60 mg/kg,

female rats up to 5 mg/kg and male rats up to 10 mg/kg, did not show any evidence of

tumourigenic

potential.

These

doses

were

associated

with

erlotinib

exposure

levels

approximately 10 and 1-2 times that anticipated clinically in mice and rats, respectively at the

maximum recommended clinical dose.

Reproductive toxicity

When erlotinib was administered during organogenesis, reduced foetal/birth weight and

increases in the incidence of small, incompletely inflated lung lobes and incomplete or absent

ossification were observed in rats at doses that resulted in plasma concentrations comparable

to those in humans. In rabbits, foetal weight was reduced at plasma concentrations 1.5 times

those of humans and the incidence of absent ossification was increased at doses producing 4.5

times the clinical exposure. Embryo/foetal lethality and/or abortion was seen in rats and rabbits

given doses that result in plasma drug concentrations 4.5 – 6.5 times those of humans.

Embryo/foetal toxicity was associated with maternal toxicity.

6.

PHARMACEUTICAL PARTICULARS

6.1.

L

IST OF EXCIPIENTS

Lactose monohydrate, microcrystalline cellulose, sodium starch glycollate type A, magnesium

stearate.

The tablets have a film-coating which contains: Opadry 200 Optimised Performance Coating

200F280000 White.

6.2.

I

NCOMPATIBILITIES

Incompatibilities were either not assessed or not identified as part of the registration for this

medicine.

200902-erlotinib sandoz-pi

Page 22 of 23

6.3.

S

HELF LIFE

In Australia, information on the shelf life can be found on the public summary of the Australian

Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4.

S

PECIAL PRECAUTIONS FOR STORAGE

Store below 30°C.

6.5.

N

ATURE AND CONTENTS OF CONTAINER

Erlotinib Sandoz 25 mg, 100 mg and 150 mg film-coated tablets are available in Aluminium-

OPA/Alu/PVC blisters containing 30 tablets.

Not all presentations are available in Australia.

6.6.

S

PECIAL PRECAUTIONS FOR DISPOSAL

The release of medicines into the environment should be minimised. Medicines should not be

disposed of via waste water and disposal through household waste should be avoided. Unused

or expired medicines should be returned to a pharmacy for disposal.

In Australia, any unused medicine or waste material should be disposed of by taking to your

local pharmacy.

6.7.

P

HYSICOCHEMICAL PROPERTIES

Chemical structure

Figure 3. Chemical structure of erlotinib hydrochloride

Erlotinib Sandoz (erlotinib hydrochloride) is an epidermal growth factor receptor/human

epidermal growth factor receptor type 1 (EGFR, also known as HER1) tyrosine kinase

inhibitor.

Erlotinib, the active ingredient of Erlotinib Sandoz, is a quinazolinamine with the chemical

name

N

-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine.

Erlotinib hydrochloride has the molecular formula C

. HCl and a molecular mass of

429.9. The molecule has a pK

of 5.42 at 25ºC. Erlotinib hydrochloride is a white to off-

white

crystalline powder, it is sparingly soluble in water, slightly soluble in methanol and

practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.

Aqueous solubility of erlotinib hydrochloride is dependent on pH, with increased solubility at

a pH < 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal

solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.

200902-erlotinib sandoz-pi

Page 23 of 23

CAS number

183319-69-9

7.

MEDICINE SCHEDULE (POISONS STANDARD)

S4 – Prescription Only Medicine

8.

SPONSOR

Sandoz Pty Ltd

ABN 60 075 449 553

54 Waterloo Road

Macquarie Park NSW 2113

Australia

Telephone No: 1800 726 369

9.

DATE OF FIRST APPROVAL

02/09/2020

10.

DATE OF REVISION

S

UMMARY TABLE OF CHANGES

Section

Changed

Summary of new information

Read the complete document

Public Summary

Summary for ARTG Entry:

326624

ERLOTINIB SANDOZ erlotinib 100 mg tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Sandoz Pty Ltd

Postal Address

54 Waterloo Road, Macquarie Park, NSW, 2113

Australia

ARTG Start Date

28/10/2020

Product Category

Medicine

Status

Active

Approval Area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods Under

Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered or

Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1 . ERLOTINIB SANDOZ erlotinib 100 mg tablet blister pack

Product Type

Single Medicine Product

Effective Date

28/10/2020

Permitted Indications

No Permitted Indications included on Record

Indication Requirements

No Indication Requirements included on Record

Standard Indications

No Standard Indications included on Record

Specific Indications

Non-small cell lung cancer

Erlotinib Sandoz is indicated for the first-line treatment of patients with advanced (Stage IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC)

with activating EGFR mutations.,Erlotinib Sandoz is indicated for maintenance therapy in patients with locally advanced or metastatic non-small cell lung

cancer (NSCLC) with activating EGFRmutations who have not progressed on first-line chemotherapy.,Erlotinib Sandoz is also indicated for the treatment of

patients with locally advanced or metastatic non- small cell lung cancer after failure of prior chemotherapy.,Pancreatic cancer

Erlotinib Sandoz in combination with gemcitabine is indicated for the treatment of patients with locally advanced, unresectable or metastatic pancreatic

cancer.

Warnings

See Product Information and Consumer Medicine Information for this product

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

PA/Al/PVC/Al -

polyamide-aluminium

foil-polyvinylchloride/al

uminium foil

18 Months

Store below 30

degrees Celsius

Neither child resistant

closure nor restricted

flow insert

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

30 tablets

(S4) Prescription Only Medicine

Components

1 . ERLOTINIB SANDOZ erlotinib 100 mg tablet blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

White to yellowish, round, biconvex, film-coated tablets with '100' engraved on one side. The diameter of the tablet is ~ 8.9

Public Summary

Page 1 of

Produced at 12.01.2021 at 07:53:33 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Active Ingredients

erlotinib hydrochloride

109.27 mg

Other Ingredients (Excipients)

lactose monohydrate

macrogol 3350

magnesium stearate

methacrylic acid copolymer

microcrystalline cellulose

polyvinyl alcohol

purified talc

sodium bicarbonate

sodium starch glycollate type A

titanium dioxide

© Commonwealth of Australia. This work is copyright. You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth. Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 2 of

Produced at 12.01.2021 at 07:53:33 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

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