Giotrif

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Afatinib dimaleate 59.12 mg equivalent to Afatinib 40 mg
Available from:
Boehringer Ingelheim (NZ) Ltd
INN (International Name):
Afatinib dimaleate 59.12 mg (= Afatinib 40 mg)
Dosage:
40 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Afatinib dimaleate 59.12 mg equivalent to Afatinib 40 mg Excipient: Colloidal silicon dioxide Crospovidone Hypromellose Indigo carmine aluminium lake Lactose monohydrate Macrogol 400 Magnesium stearate Microcrystalline cellulose Polysorbate 80 Purified talc Titanium dioxide
Prescription type:
Prescription
Manufactured by:
Boehringer Ingelheim Pharma GmbH & Co KG
Therapeutic indications:
GIOTRIF is indicated as monotherapy for the treatment of patients with: Locally advanced or metastatic non-squamous non-small cell carcinoma of the lung, either as first line therapy or after failure of cytotoxic chemotherapy. Tumours must have Epidermal Growth Factor Receptor (EGFR) mutations. Locally advanced or metastatic non-small cell carcinoma of the lung of squamous histology progressing on or after platinum-based chemotherapy.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PvDC/Al blister sheet in Alu laminate pouch in carton - 7 tablets - 36 months from date of manufacture stored at or below 30°C protect from light - Blister pack, PVC/PvDC/Al blister sheet in Alu laminate pouch in carton - 14 tablets - 36 months from date of manufacture stored at or below 30°C protect from light - Blister pack, PVC/PvDC/Al blister sheet in Alu laminate pouch in carton - 28 tablets - 36 months from date of manufacture stored at or below 30°C protect from light
Authorization number:
TT50-9477b
Authorization date:
2014-01-06

Read the complete document

GIOTRIF NZ CMI v02

GIOTRIF

®

Film-coated Tablets

afatinib (as dimaleate)

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Giotrif.

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 this medicine

against the expected benefits.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

This leaflet was last updated on the

date at the end of this leaflet. More

recent information may be available.

The latest Consumer Medicine

Information is available from your

pharmacist, doctor or from

www.medsafe.govt.nz/

Consumers/cmi/CMIForm.asp and

may contain important information

about the medicine and its use of

which you should be aware.

Keep this information with the

medicine.

You may need to read it again.

What Giotrif is used

for

Giotrif contains the active substance

afatinib (as afatinib dimaleate).

Giotrif belongs to a group of

medicines called antineoplastic (or

anti-cancer) agents.

It works by blocking the activity of a

group of proteins from the ErbB

family, which includes a protein

called Epidermal Growth Factor

Receptor (EGFR). These proteins are

known to be involved in the growth

and spread of cancer cells. By

blocking the activity of these proteins

Giotrif stops the cancer cells from

growing and multiplying.

Giotrif is used to treat adult patients

with a type of lung cancer called

non-small cell lung cancer (NSCLC):

of non-squamous type identified

with a change (mutation) in the

gene for EGFR. Giotrif can be

prescribed to you as your first

treatment or if your cancer has

progressed after receiving

chemotherapy

of squamous type if your cancer

has progressed after receiving

chemotherapy.

Ask your doctor if you have any

questions about why Giotrif has

been prescribed for you.

Your doctor may have prescribed

Giotrif for another reason.

This medicine is available only with

a doctor's prescription.

Before you take Giotrif

When you must not take it

Do not take Giotrif if you have

ever had an allergy to:

afatinib dimaleate (the active

ingredient) or

any of the other ingredients listed

at the end of this leaflet.

Some of the 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.

Do not take this medicine if you

are pregnant.

It may affect your developing baby if

you take it during pregnancy.

If you are a woman who could

become pregnant, use adequate

contraception during Giotrif

treatment and for at least 2 weeks

after taking the last dose.

Do not breast-feed if you are

taking this medicine.

The active ingredient in Giotrif may

pass into breast milk and there is a

possibility that your baby may be

affected.

Do not give this medicine to a child

under the age of 18 years.

Safety and effectiveness in children

younger than 18 years have not been

established.

Do not take this medicine after the

expiry date printed on the pack or

if the packaging is torn or shows

signs of tampering.

If it has expired or is damaged, return

it to your pharmacist for disposal.

If you are not sure whether you

should start taking this medicine,

talk to your doctor.

GIOTRIF NZ CMI v02

Before you start to take it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if you:

have any liver problems

have any kidney problems

have a history of heart problems

have a history of lung

inflammation (interstitial lung

disease)

have a history of gastrointestinal

problems

are receiving medicines which

could increase the risk of

developing a hole in the wall of

your gut, such as steroids (used to

treat inflammation and allergies),

NSAIDs (used to relieve pain,

swelling and other symptoms of

inflammation, including arthritis)

or anti-angiogenic agents (used to

treat cancer)

have or have had cancer that has

spread to the bowel

use contact lenses and/or have a

history of eye problems such as

severe dry eyes, inflammation of

the front part of the eye (cornea)

or ulcers involving the front part

of the eye

cannot tolerate lactose

monohydrate.

If you have not told your doctor

about any of the above, tell them

before you start taking Giotrif.

Your doctor may want to take special

precautions if you have any of the

above conditions.

It is likely that your doctor will also

prescribe an anti-diarrhoeal medicine

(e.g. loperamide) for you to take in

case you get diarrhoea after starting

treatment with Giotrif.

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 or health food

shop.

Some medicines and Giotrif may

interfere with each other. These

include:

ritonavir, nelfinavir or saquinavir,

medicines used to treat HIV

infections

ciclosporin or tacrolimus,

medicines used to suppress the

immune system

ketoconazole or itraconazole,

medicines used to treat fungal

infections

erythromycin or rifampicin,

medicines used to treat infections

verapamil, a medicine used to

treat high blood pressure and

angina

amiodarone, a medicine used to

treat irregular heartbeats

carbamazepine, phenytoin or

phenobarbital, medicines used to

treat fits or convulsions

herbal medicines derived from St

John’s wort (Hypericum

perforatum)

quinidine, a medicine used to

treat irregular heartbeats

sulfasalazine, a medicine used to

treat inflammation

rosuvastatin, a medicine used for

lowering cholesterol.

These medicines may be affected by

Giotrif or may affect how well it

works. You may need different

amounts of your medicines, or you

may need to take different medicines.

Your doctor and pharmacist will

have more information on medicines

to be careful with or avoid while

taking this medicine.

How to take Giotrif

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the

information contained in this leaflet.

If you do not understand the

instructions on the box, ask your

doctor or pharmacist for help.

How much to take

The recommended dose is one tablet

of Giotrif 40 mg each day.

Your doctor may adjust (increase or

decrease) your dose depending on

how well you tolerate Giotrif. If you

get severe diarrhoea or other

intolerable side effects, your doctor

may interrupt your treatment with

Giotrif and then re-start your

treatment at a lower dose.

How to take it

Swallow the tablet whole with a

full glass of water. Do not chew or

crush the tablets.

For patients with swallowing

difficulties the tablet can be

dissolved in drinking water (non-

carbonated). No other liquids

should be used. Follow these

instructions carefully:

Drop the tablet into half a glass of

drinking water (non-carbonated)

(Do not break or crush the tablet)

Stir the water occasionally for up

to 15 minutes until the tablet is

broken up into very small

particles

Drink the liquid straight away

Rinse the empty glass with half a

glass of drinking water and drink

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

Take your medicine on an empty

stomach. Do not eat for at least 3

hours before taking your medicine

and at least 1 hour after taking

your medicine.

GIOTRIF NZ CMI v02

Food can interfere with the

absorption of this medicine.

How long to take it

Continue taking your medicine for

as long as your doctor tells you.

If you forget to take it

If it is less than 8 hours before your

next dose, skip the dose you missed

and take your next dose when you

are meant to.

Otherwise, take it as soon as you

remember, and then go back to

taking your medicine as you would

normally.

Do not take a double dose to make

up for the dose that you missed.

This may increase the chance of you

getting an unwanted side effect.

If you are not sure what to do, ask

your doctor or pharmacist.

If you have trouble remembering

to take your medicine, ask your

pharmacist for some hints.

If you take too much

(overdose)

Immediately telephone your doctor

or the Poisons Information Centre

(telephone 0800 764 766) for

advice, or go to Emergency at the

nearest hospital if you think that

you or anyone else may have taken

too much Giotrif. Do this even if

there are no signs of discomfort or

poisoning.

You may need urgent medical

attention.

While you are taking

Giotrif

Things you must do

If you are about to be started on

any new medicine, tell your doctor

or pharmacist that you are taking

Giotrif.

Tell any other doctors, dentists and

pharmacists who treat you that

you are taking this medicine.

If you go into hospital, tell the

medical staff that you are taking

this medicine.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

Things you must not do

Do not take Giotrif to treat any

other complaints unless your

doctor tells you to.

Do not give your medicine to

anyone else, even if they have the

same condition as you.

Do not stop taking your medicine

or lower the dosage without

checking with your doctor.

Things to be careful of

Limit your exposure to sunlight

while you are taking Giotrif. When

you are outdoors, wear a hat,

protective clothing and sunscreen.

Giotrif may cause your skin to be

much more sensitive to sunlight than

it normally is. Rash or acne may

occur or worsen in areas exposed to

the sun.

Be careful driving, operating

machinery or doing jobs that

require you to be alert until you

know how Giotrif affects you.

No studies on the effects of Giotrif

on the ability to drive and operate

machinery have been performed.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking Giotrif.

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.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

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:

skin reactions such as acne-like

rash, sometimes itchy with dry

skin

mouth sores and inflammation

problems with your nails

loss of appetite or weight changes

bleeding from the nose

pain, redness swelling or peeling

of the skin of your hands and feet

burning sensations during

urination and frequent, urgent

need to urinate

abnormal taste sensations

stomach pain, indigestion,

heartburn

lip inflammation

runny nose

muscle spasms

fever

nausea

vomiting.

Giotrif may be associated with

changes in your blood, urine or liver

test results. Your doctor may want to

perform tests from time to time to

check on your progress and detect

any unwanted side effects.

Tell your doctor immediately if

you notice any of the following:

diarrhoea (usually occurs within

the first 2 to 6 weeks of

treatment)

any signs and symptoms of

dehydration such as headache,

dizziness, tiredness or decreased

urine output

severe skin reactions such as

peeling or blistering of the skin

severe pain in your stomach area,

fever, chills, sickness, vomiting,

GIOTRIF NZ CMI v02

or abdominal rigidity or bloating,

this could be symptoms of a hole

in the wall of your gut

('gastrointestinal perforation')

sudden or worse eye problems

such as irritated, red, runny or

itchy eyes, blurred vision,

swollen or crusty eyelid, or dry

a combination of any of the

following: breathlessness,

swelling of the feet, ankles, legs

or stomach, feeling tired, a

feeling like your heart is racing or

throbbing.

Diarrhoea is a very common side

effect of Giotrif and this is

sometimes severe. You may become

dehydrated if you experience severe

or persistent diarrhoea and this could

become serious and life-threatening

if untreated.

As soon as you notice any signs of

diarrhoea, you should drink plenty

of fluids and take the anti-

diarrhoeal medicine exactly as

your doctor tells you to help treat

your diarrhoea.

You must immediately ask your

doctor for further advice if your

diarrhoea becomes severe (with

more than 4 bowel movements

each day) or if your diarrhoea is

not under control within 48 hours

after taking the anti-diarrhoeal

medicine.

Tell your doctor immediately or go

to Emergency at your nearest

hospital if you experience sudden

difficulty in breathing or

unexplained breathing problems

associated with cough or fever.

Some patients taking Giotrif have

experienced a rare form of lung

inflammation called interstitial lung

disease which is a serious side effect.

This side effect is uncommon. You

may need urgent medical attention or

hospitalisation.

Tell your doctor immediately or go

to Emergency at your nearest

hospital if you experience:

severe upper stomach pain

radiating to the back, nausea,

vomiting, or fever (which may be

symptoms of an inflamed

pancreas - pancreatitis)

severe blisters and bleeding in the

lips, eyes, mouth, nose and

genitals

painful red areas of the skin, large

blisters and peeling of the skin,

accompanied by fever and chills,

aching muscles and generally

feeling unwell.

These side effects are uncommon.

You may need urgent medical

attention or hospitalisation.

Tell your doctor or pharmacist if

you notice anything else that is

making you feel unwell.

Other side effects not listed above

may also occur in some people.

After taking Giotrif

Storage

Keep your tablets in the blister

pack until it is time to take them to

protect from moisture and light.

If you take the tablets out of the

blister pack they may not keep well.

Keep your tablets in a cool dry

place where the temperature stays

below 30°C.

Do not store Giotrif or any other

medicine in the bathroom or near a

sink. Do not leave it on a window

sill or in the car.

Heat and dampness can destroy some

medicines.

Keep it where 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 this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

that is left over.

Product Description

What it looks like

Giotrif is the brand name of your

medicine.

Giotrif is available in four strengths

of film-coated tablets:

Giotrif 20 mg - white to slightly

yellowish, round tablets, imprinted

with a "T20" code on one side and

the company logo on the other side.

Giotrif 30 mg - dark blue, round

tablets, imprinted with a "T30" code

on one side and the company logo on

the other side.

Giotrif 40 mg - light blue, round

tablets, imprinted with a "T40" code

on one side and the company logo on

the other side.

Giotrif 50 mg - dark blue, oval

tablets, imprinted with a "T50" code

on one side and the company logo on

the other side.

Giotrif is packed in blister foils of 7,

14 and 28 tablets. Each blister foil is

packed together with a desiccant

sachet in a protective foil pouch.

Not all pack sizes may be marketed.

Ingredients

Active ingredient:

Giotrif 20 mg - 20 mg afatinib (as

29.56 mg afatinib dimaleate) per

tablet.

Giotrif 30 mg - 30 mg afatinib (as

44.34 mg afatinib dimaleate) per

tablet.

Giotrif 40 mg - 40 mg afatinib (as

59.12 mg afatinib dimaleate) per

tablet.

Giotrif 50 mg - 50 mg afatinib (as

73.9 mg afatinib dimaleate) per

tablet.

Inactive ingredients:

Each tablet also contains:

GIOTRIF NZ CMI v02

lactose monohydrate

microcrystalline cellulose

colloidal silicon dioxide

crospovidone

magnesium stearate.

The tablets also have a film-coating

which contains:

hypromellose

macrogol 400

titanium dioxide

purified talc

polysorbate 80

colourant containing indigo

carmine aluminium lake (only

used for 50 mg, 40 mg and 30 mg

tablets).

Supplier

Giotrif is supplied in New Zealand

Boehringer Ingelheim (N.Z.) Ltd

Auckland

® Giotrif is a registered trade mark

of Boehringer Ingelheim.

© Boehringer Ingelheim 2019.

This Consumer Medicine

Information was updated in May

2019.

Read the complete document

GIOTRIF NZ DS v05

NEW ZEALAND DATASHEET

1. PRODUCT NAME

GIOTRIF 20 mg film-coated tablets

GIOTRIF 30 mg film-coated tablets

GIOTRIF 40 mg film-coated tablets

GIOTRIF 50 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

GIOTRIF 20 mg film-coated tablets

One film-coated tablet contains 20 mg afatinib (as dimaleate)

Excipient

with

known

effect:

film-coated

tablet

contains

123.86

lactose

monohydrate

GIOTRIF 30 mg film-coated tablets

One film-coated tablet contains 30 mg afatinib (as dimaleate)

Excipient

with

known

effect:

film-coated

tablet

contains

185.79

lactose

monohydrate

GIOTRIF 40 mg film-coated tablets

One film-coated tablet contains 40 mg afatinib (as dimaleate)

Excipient

with

known

effect:

film-coated

tablet

contains

247.72

lactose

monohydrate

GIOTRIF 50 mg film-coated tablets

One film-coated tablet contains 50 mg afatinib (as dimaleate)

Excipient

with

known

effect:

film-coated

tablet

contains

309.65

lactose

monohydrate

For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

GIOTRIF 20 mg film-coated tablets

White to slightly yellowish, round, biconvex and bevel-edged film-coated tablet debossed with

the code “T20” on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF 30 mg film-coated tablets

Dark blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T30”

on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF 40 mg film-coated tablets

Light blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T40”

on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF 50 mg film-coated tablets

Dark blue, oval and biconvex film-coated tablet debossed with the code “T50” on one side and

the Boehringer Ingelheim company logo on the other.

Afatinib dimaleate is a white to brownish yellow powder. It is highly soluble in water and

in aqueous buffer media up to pH 6 (> 50 mg/mL). Between pH 6 and 7, the solubility in

these media decreases significantly but still exceeds 1 mg/mL. Above pH 7, solubility is

reduced further to the low solubility of its free base (0.04 mg/mL at pH > 8). The highest

GIOTRIF NZ DS v05

solubility in organic solvents is observed for DMSO (> 50 mg/mL). Solubility in methanol is

between 10 and 25 mg/mL; in 1:1 mixtures of acetonitrile, methanol, and ethanol with water

the solubility exceeds 50 mg/mL. Dissociation constants: pKa1 = 8.2 ± 0.1; pKa2 = 5.0 ± 0.1.

Partition coefficient: log P = 4.7 (at pH ≥ 9); log D = 3.8 (at pH 7.4).

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

GIOTRIF is indicated as monotherapy for the treatment of patients with:

Locally advanced or metastatic non-squamous non-small cell carcinoma of the lung,

either as first line therapy or after failure of cytotoxic chemotherapy. Tumours must

have Epidermal Growth Factor Receptor (EGFR) mutations.

Locally advanced or metastatic non-small cell carcinoma of the lung of squamous

histology progressing on or after platinum-based chemotherapy.

4.2 Dose and method of administration

Dose

The recommended dose of GIOTRIF is 40 mg orally once daily for first-line treatment or

for patients not previously treated with an EGFR Tyrosine Kinase Inhibitor (EGFR TKI-naïve

patients) and for patients with squamous NSCLC who have previously received first-line

platinum-containing regimen.

GIOTRIF should be taken without food. Food should not be consumed for at least 3

hours before and at least 1 hour after taking GIOTRIF (see sections 5.2 and 4.4). Tablets

should be swallowed whole with water.

GIOTRIF treatment

should

continued

until

disease

progression

until

longer

tolerated by the patient (see Table 1 below).

Dose escalation

A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a

40 mg/day starting dose (i.e. absence of diarrhoea, skin rash, stomatitis and other drug

related events of CTCAE Grade > 1) in the first cycle of treatment (for the definition of

treatment cycle see Section 5 Pharmacological Properties). The dose should not be

escalated in patients with a prior dose reduction.

The maximum daily dose in any setting is 50 mg.

Dose adjustment for adverse reactions

Symptomatic adverse drug reactions (e.g. severe/persistent diarrhoea or skin-related adverse

reactions) may be successfully managed by treatment interruption and dose reductions of

GIOTRIF as outlined in Table 1 (see sections 4.8 and 4.4).

GIOTRIF NZ DS v05

Table 1:

Dose Adjustment Information for Adverse Reactions

CTCAE

a

Drug

Related

Adverse

Event

Recommended Dosing of GIOTRIF

Grade 1 or Grade 2

No interruption

No dose adjustment

Grade 2 (prolonged

or intolerable) or

Grade ≥ 3

Interrupt until Grade 0/1

Resume with dose reduction

by 10 mg decrements

NCI Common Terminology Criteria for Adverse Events v 3.0

In case of diarrhoea, antidiarrhoeal medicines (e.g. loperamide) should be taken immediately and continued for

persistent diarrhoea until loose bowel movements cease.

> 48 hours of diarrhoea and/or > 7 days of rash

If patient cannot tolerate 20 mg/day, permanent discontinuation of GIOTRIF should be considered

Interstitial Lung Disease (ILD) should be considered if a patient develops acute or worsening

of respiratory symptoms in which case GIOTRIF should be interrupted pending evaluation.

If ILD is diagnosed, GIOTRIF should be discontinued and appropriate treatment instituted as

necessary (see section 4.4).

Missed dose

If a dose of GIOTRIF is missed, it should be taken during the same day as soon as the patient

remembers. However, if the next scheduled dose is due within 8 hours then the missed

dose must be skipped.

Patients with renal impairment

Exposure to afatinib was found to be increased in patients with moderate or severe renal

impairment (see section 5.2). Adjustments to the starting dose are not necessary in patients

with mild, moderate or severe (eGFR 15-29 mL/min/1.73m

) renal impairment. Monitor

patients with severe renal impairment and adjust GIOTRIF dose if not tolerated. GIOTRIF

treatment in patients with eGFR <15 mL/min/1.73m

or on dialysis is not recommended.

Patients with hepatic impairment

Exposure to afatinib is not significantly changed in patients with mild (Child Pugh A) or

moderate (Child Pugh B) hepatic impairment (see section 5.2). Adjustments to the starting

dose are not necessary in patients with mild or moderate hepatic impairment. GIOTRIF has

not been studied in patients with severe (Child Pugh C) hepatic impairment. GIOTRIF

treatment in this population is not recommended.

Age, Race, Gender

No dose adjustment is necessary based on patient age, race, or gender (see section 5.2

Paediatric population

safety

efficacy

GIOTRIF

have

been

studied

paediatric

patients.

Therefore, treatment of children or adolescents with GIOTRIF is not recommended.

Use of P-glycoprotein (P-gp) inhibitors

If P-gp inhibitors need to be taken, they should be administered simultaneously with or

after GIOTRIF (see sections 5.2, 4.4 and 4.5).

Method of administration

GIOTRIF is for oral use. The tablets should be swallowed whole with water. If swallowing of

whole tablets is not possible, GIOTRIF tablets can be dispersed in approximately 100 mL of

non-carbonated drinking water. No other liquids should be used. The tablet should be dropped

into the water without crushing it, and stirred occasionally for up to 15 minutes until the tablet

is broken up into very small particles. The dispersion should be consumed immediately. The

glass should be rinsed with approximately 100 mL of water which should also be consumed.

The dispersion can also be administered through a gastric tube.

GIOTRIF NZ DS v05

4.3 Contraindications

GIOTRIF is contraindicated in patients with known hypersensitivity to afatinib or to any of the

excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Assessment of EGFR mutation status

When assessing the EGFR mutation status of a patient, it is important that a well-validated

and robust methodology is chosen to avoid false negative or false positive determinations.

Diarrhoea

Diarrhoea, including severe diarrhoea, has been reported during treatment with GIOTRIF (see

section 4.8). Diarrhoea may result in electrolyte abnormalities and/or dehydration with or

without renal impairment, which in rare cases has resulted in fatal outcomes. Monitoring for

serum electrolyte abnormalities may be required depending on the severity and duration of

diarrhoea. Diarrhoea usually occurred within the first 2 weeks of treatment. Grade 3 diarrhoea

most frequently occurred within the first 6 weeks of treatment. Proactive management of

diarrhoea including adequate hydration combined with antidiarrhoeal agents especially within

the first six weeks of the treatment is important and should start at first signs o

f diarrhoea.

Antidiarrhoeal agents (e.g. loperamide) should be used and if necessary their dose should be

escalated to the highest recommended approved dose. Antidiarrhoeal agents should be

readily available to the patients so that treatment can be initiated at first signs of diarrhoea

and continued until loose bowel movements cease for 12 hours. Patients with severe

diarrhoea may require interruption and dose reduction or discontinuation of therapy with

GIOTRIF (see section 4.2). Patients who become dehydrated may require administration of

intravenous electrolytes and fluids.

Skin related adverse events

Rash/acne has been reported in patients treated with GIOTRIF (see section 4.8). In general,

rash manifests as a mild or moderate erythematous and acneiform rash, which may occur or

worsen in areas exposed to sun. For patients who are exposed to sun, protective clothing,

and/or use of sun screen is advisable. Early intervention (e.g. emollients, antibiotics) of

dermatologic reactions can facilitate continuous GIOTRIF treatment.

Patients with prolonged or severe skin reactions may also require temporary interruption of

therapy, dose reduction (see section 4.2), additional therapeutic intervention, and referral to

a specialist with expertise in managing these dermatologic effects. Bullous, blistering and

exfoliative skin conditions have been reported including rare cases suggestive of Stevens-

Johnson syndrome and toxic epidermal necrolysis. GIOTRIF treatment should be interrupted

or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

Female gender, lower body weight and underlying renal impairment

Higher exposure to afatinib has been observed in female patients, patients with lower body

weight and those with underlying renal impairment (see section 5.2). This could result in a

higher risk of developing EGFR-mediated adverse events such as diarrhoea, rash/acne and

stomatitis. Closer monitoring is recommended in patients with these risk factors.

Interstitial Lung Disease (ILD)

There have been reports of ILD or ILD-like events (such as Lung infiltration, Pneumonitis,

Acute Respiratory Distress Syndrome, Alveolitis allergic), including fatalities, in patients

receiving GIOTRIF for treatment of NSCLC. Drug-related ILD-like events were reported in

0.7% of patients treated with GIOTRIF across all clinical trials (including 0.5% of patients with

CTCAE Grade ≥ 3 ILD-like adverse reactions) (see section 4.8). Patients with a history of ILD

have not been studied. Careful assessment of all patients with an acute onset and/or

unexplained

worsening

pulmonary

symptoms

(dyspnoea,

cough,

fever)

should

performed to excl

ude ILD. GIOTRIF should be interrupted pending investigation of these

GIOTRIF NZ DS v05

symptoms. If ILD is diagnosed, GIOTRIF should be permanently discontinued and appropriate

treatment instituted as necessary (see section 4.2).

Severe hepatic impairment

Hepatic failure, including fatalities, has been reported during treatment with GIOTRIF in

less than 1% of patients. In these patients, confounding factors have included pre-existing

liver disease and/or co-morbidities associated with progression of underlying malignancy.

Periodic liver function testing is recommended in patients with pre-existing liver disease.

GIOTRIF dose interruption may become necessary in patients who experience worsening of

liver function (see section 4.2). In patients who develop severe hepatic impairment while

taking GIOTRIF, treatment shoul

d be discontinued.

Gastrointestinal perforations

Gastrointestinal perforation, including fatalities, has been reported during treatment with

GIOTRIF in 0.2% of patients across all randomised controlled clinical trials. In the majority of

cases, gastrointestinal perforation was associated with other known risk factors, including

concomitant medications such as corticosteroids, NSAIDs, or anti-angiogenic agents, an

underlying history of gastrointestinal ulceration, underlying diverticular disease, age, or bowel

metastases at sites of perforation. In patients who develop gastrointestinal perforation while

taking GIOTRIF, treatment should be permanently discontinued.

Keratitis

Symptoms such as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred

vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If

a diagnosis of ulcerative keratitis is confirmed, treatment with GIOTRIF should be interrupted

or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should

be carefully considered. GIOTRIF should be used with caution in patients with a history

of keratitis, ulcerative keratitis or severe dry eye. Contact lens u

se is also a risk factor for

keratitis and ulceration (see section 4.8).

Left ventricular function

Left ventricular dysfunction has been associated with HER2 inhibition. GIOTRIF has not been

studied in patients with abnormal left ventricular ejection fraction (LVEF) or those with

significant cardiac history. In patients with cardiac risk factors and those with conditions

that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and

during GIOTRIF treatment, should be considered. In patients who develop relevant cardiac

signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be

considered.

In patients with an ejection fraction below the institution’s lower limit of normal, cardiac

consultation

well

GIOTRIF

treatment

interruption

discontinuation

should

considered.

Pancreatitis

Adverse events of pancreatitis have been observed uncommonly in patients treated with

GIOTRIF.

Although

causal

association

established,

patients

develop

symptoms consistent with the diagnosis should be evaluated for pancreatitis.

P-glycoprotein (P-gp) interactions

Concomitant treatment with strong inducers of P-gp may decrease exposure to afatinib

(see sections 4.2 and 4.5).

Lactose monohydrate

GIOTRIF

contains

lactose monohydrate. Patients

with

rare

hereditary

conditions

galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should

not take this medicine.

GIOTRIF NZ DS v05

4.5 Interaction with other medicines and other forms of interaction

P-glycoprotein (P-gp) interactions

Based on in vitro data, afatinib is a substrate of P-gp. Based on clinical data, concomitant

administration of strong P-gp inhibitors or inducers may alter exposure to afatinib. Results of

a drug interaction trial demonstrated that GIOTRIF can be safely combined with P-gp

inhibitors (such as ritonavir) as long as the inhibitor is administered simultaneously with or

after GIOTRIF. If administered prior to GIOTRIF, strong P-gp inhibitors (including but not

limited

ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin,

verapamil,

quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) may increase exposure to

afatinib and should be used with caution (see sections 5.2, 4.4 and 4.2).

Strong P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin,

phenobarbital or St. John’s Wort) may decrease exposure to afatinib (see sections 5.2 and

4.4).

Interactions with breast cancer resistance protein (BCRP)

In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP.

Afatinib may increase the bioavailability of orally administered BCRP substrates (including

but not limited to rosuvastatin and sulfasalazine) and caution should be exercised when co-

administrating GIOTRIF and BCRP substrates.

Food effect on afatinib

Co-administration of a high-fat meal with GIOTRIF resulted in a significant decrease of

exposure to afatinib by about 50% in regard to Cmax and 39% in regard to AUC

0-∞

. GIOTRIF

should be administered without food (see sections 5.2 and 4.2).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

treatment with GIOTRIF. Adequate contraceptive methods should be used during therapy and

for at least 2 weeks after the last dose.

Pregnancy (Category C)

Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal

harm. Animal studies with afatinib did not indicate direct or indirect harmful effects with

respect to reproductive toxicity (see section 5.3). Studies in animals have shown no signs

of teratogenicity up to and including maternally lethal dose levels. Adverse changes were

restricted to toxic dose levels. However, systemic exposures achieved in animals were

either in a similar range or below the levels observed in patients (see section 5.3).

There are no studies in pregnant women using GIOTRIF. It is unknown whether afatinib

crosses the placenta in humans. The potential risk for humans is thus unknown. If GIOTRIF

is used during pregnancy or if the patient becomes pregnant while receiving GIOTRIF, the

patient should be apprised of the potential hazard to the foetus.

Breast-feeding

Available pharmacokinetic data in animals have shown excretion of afatinib in milk (see section

5.3). Based on this, it is likely that afatinib is excreted in human milk. A risk to the breast-feeding

child cannot be excluded. Mothers should be advised against breast-feeding while receiving this

medicinal product.

Fertility

Fertility studies in humans have not been performed with GIOTRIF. Available nonclinical

GIOTRIF NZ DS v05

toxicology data have shown effects on reproductive organs at higher doses. Therefore, an

adverse effect of GIOTRIF therapy on human fertility cannot be excluded.

4.7 Effects on ability to drive and use machines

GIOTRIF has minor influence on the ability to drive and use machines. During treatment, ocular

adverse reactions (conjunctivitis, dry eye, keratitis) have been reported in some patients (see

section 4.8) which may affect patients ability to drive or use machines.

4.8 Undesirable Effects

Summary of the safety profile

The safety evaluation of GIOTRIF is based on the data from clinical trials and post marketing

experience.

Controlled studies

In the pivotal LUX-Lung 3 (1200.32) trial a total of 229 EGFR TKI naïve patients were treated

with GIOTRIF with a starting dose of 40 mg once daily. A total of 111 patients were treated

with pemetrexed/cisplatin. The overall incidence of Adverse Drug Reactions (ADRs) in

patients treated with GIOTRIF was similar to pemetrexed/cisplatin (100% vs. 96%). The

incidence of diarrhoea (95% vs. 15%) and rash/acne (89% vs. 6%) ADRs were higher in the

GIOTRIF-treated

patients

than

those

patients

treated

with

pemetrexed/cisplatin,

respectively. Dose reductions due to adverse events occurred in 57% of GIOTRIF-treated

patients. Overall dose reduction led to a lower frequency of

common adverse events (e.g.

after first dose reduction, frequency for diarrhoea regardless of causality decreased from 96%

to 52%).

Elderly patients may be more likely to experience a higher grade of the more frequent EGFR

TKI-associated events. Grade 3 AEs were observed in 67% in patients ≥70 years of age

versus 47% in patients <70 years of age.

Discontinuation of therapy due to ADRs was lower in patients who received once daily

GIOTRIF 40 mg compared with pemetrexed/cisplatin (8% vs. 12%). In patients treated with

GIOTRIF, discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0%,

respectively.

In the LUX-Lung 6 (1200.34) trial a total of 239 EGFR TKI naïve patients were treated with

GIOTRIF with a starting dose of 40 mg once daily. A total of 113 patients were treated with

gemcitabine/cisplatin. The overall incidence of ADRs in patients treated with GIOTRIF was

similar to gemcitabine/cisplatin (98.7% vs. 99.1%). The incidences of diarrhoea (88.7% vs.

10.6%) and rash/acne (81.2% vs. 8.8%) ADRs were higher in the GIOTRIF-treated patients

than in patients treated with gemcitabine/cisplatin. Dose reductions due to adverse events

occurred in 33.1% of GIOTRIF-treated patients and in 26.5% of gemcitabine/cisplatin-treated

patients.

Discontinuations of study medication due to ADRs were less frequent in patients who received

GIOTRIF compared with gemcitabine/cisplatin (6.3% vs. 39.8%). In patients treated with

GIOTRIF, the incidences of discontinuations due to the ADRs diarrhoea and rash/acne were

0% and 2.5%, respectively.

In the pivotal LUX-Lung 8 (1200.125) trial a total of 392 patients with squamous NSCLC were

treated with GIOTRIF with a starting dose of 40 mg once daily and a total of 395 patients were

treated with 150 mg erlotinib once daily. After the first treatment cycle (28 days) the dose of

GIOTRIF was escalated to 50 mg in 39 (10%) patients. The overall incidence of ADRs in

patients treated with GIOTRIF or erlotinib was 93% vs. 81% respectively. The incidence of

diarrhoea ADRs was higher in the GIOTRIF-treated patients compared to erlotinib (70% vs.

33%), while incidence of rash/acne was similar in both groups (67% vs. 67%). Dose

GIOTRIF NZ DS v05

reductions due to adverse events occurred in 27% of GIOTRIF-treated patients. Treatment

was discontinued due to ADRs in 11% of patients treated with GIOTRIF, and in 5% of erlotinib

treated patients.

Description of selected adverse reactions

Very Common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial

LUX-LUNG 3 are summarised by National Cancer Institute – Common Terminology Criteria

(NCI-CTC) Grade in Table 2.

Table 2: Adverse Events Reported in ≥10% of GIOTRIF Treated Patients in LUX-Lung 3

GIOTRIF N=229

Pemetrexed/Cisplatin

N=111

Adverse Event

All

Grades

(%)

Grade 3

(%)

Grade 4

(%)

All

Grades

(%)

Grade 3

(%)

Grade 4

(%)

Gastrointestinal disorders

Diarrhoea

Stomatitis

Nausea

Vomiting

Constipation

Cheilitis

Skin and subcutaneous tissue disorders

Rash

Dermatitis acneiform

Pruritus

Dry skin

Alopecia

Infections and infestations

Paronychia

Nasopharyngitis

Cystitis

Upper respiratory tract infection

Metabolism and nutrition disorders

Decreased appetite

Hypokalemia

General disorders and administration site conditions

Fatigue

Pyrexia

Respiratory, thoracic and mediastinal disorders

Epistaxis

Cough

Rhinorrhea

Investigations

Weight decreased

Alanine aminotransferase

Psychiatric disorders

Insomnia

GIOTRIF NZ DS v05

GIOTRIF N=229

Pemetrexed/Cisplatin

N=111

Adverse Event

All

Grades

(%)

Grade 3

(%)

Grade 4

(%)

All

Grades

(%)

Grade 3

(%)

Grade 4

(%)

Nervous system disorder

Headache

Dizziness

Musculoskeletal and connective tissue disorders

Back pain

Eye disorders

Conjunctivitis

Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion,

mucosal erosion, mucosal ulceration

Includes group of rash preferred terms

Includes acne, acne pustular, dermatitis acneiform

Includes pruritus, pruritus generalized

Includes dry skin, skin chapped

Includes paronychia, nail infection, nail bed infection

Includes cystitis, urinary tract infection

Includes hypokalemia, blood potassium decreased

Includes rhinorrhea, nasal inflammation

Includes pyrexia, body temperature increased

Includes conjunctivitis, conjunctival irritation, conjunctival hyperemia

All NSCLC-studies with daily dose of 40 mg or 50 mg GIOTRIF

The safety of GIOTRIF monotherapy at starting doses of 40 mg or 50 mg once daily was

assessed in pooled analyses of NSCLC trials in patients with or enriched for EGFR mutations.

The predominant type of histology in this patient population was adenocarcinoma of the lung.

The types of ADRs were generally associated with the EGFR inhibitory mode of action of

afatinib and the profile of ADRs was consistent with the LUX-Lung 3 trial. CTCAE Grade 1 or

2 ADRs occurred in 58.8% of patients treated with GIOTRIF 40 mg. CTCAE Grade 3 or 4 ADRs

occurred in 38% of patients treated with GIOTRIF 40 mg. The majority of ADRs were of CTCAE

Grade 1 or 2. ADRs were manageable as described in sections 4.2 and 4.4 which was reflected

in the low treatment discontinuation rate of 7% due to ADRs.

A summary of common ADRs of diarrhoea and rash/acne in EGFR mutation positive or

enriched population with NSCLC treated with GIOTRIF monotherapy is provided in Table 3.

Table 3:

Pooled analyses of drug related diarrhoea and rash/acne in EGFR

mutation positive or enriched NSCLC population receiving GIOTRIF

monotherapy in clinical studies

EGFR

TKI-naïve

(Starting

dose

40

mg/day)

N=497

CTCAE

a

Grade 3 rash/acne

14.3%

CTCAE

a

Grade 3 diarrhoea

9.9%

Discontinuation due to rash/acne (all Grades)

1.2%

Discontinuation due to diarrhoea (all Grades)

0.6%

NCI Common Terminology Criteria for Adverse Events v 3.0

GIOTRIF NZ DS v05

One patient (0.2%) receiving a 40 mg starting dose experienced Grade 4 rash/acne.

The safety of GIOTRIF monotherapy in patients with squamous cell carcinoma of the lung

receiving 40 mg starting dose was assessed in trial LUX-Lung 8. The most frequent ADRs

were associated with the EGFR inhibitory mode of action of GIOTRIF and were consistent with

trial LUX-Lung 3 in patients with adenocarcinoma of the lung. The majority of patients with

ADRs (65%) had Grade 1 or 2 events. The ADR of CTCAE grade 3 / 4 diarrhoea occurred in

9.9% / 0.5% of patients. The rate of drug-related CTCAE grade 3 rash was 5.9%. ADRs led to

discontinuation of treatment for 11% of patients. Discontinuation of treatment due to ADRs

diarrhea and rash/acne regardless of severity grade occurred in 3.8% and 2.0% of patients.

Tabulated list of adverse reactions

The ADRs pooled from all NSCLC trials with daily GIOTRIF doses as monotherapy

(N=2135) and post-marketing experience are shown below by system organ class. The

frequency categories used are defined as: Very common (≥1/10); Common (≥1/100 to <1/10);

Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000).

GIOTRIF NZ DS v05

Body System

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Infections and

infestations

Paronychia

Cystitis

Metabolism and

nutrition disorders

Decreased

appetite

Dehydration

Hypokalemia

Nervous system

disorders

Dysgeusia

Eye disorders

Conjunctivitis

Dry eye

Keratitis

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis

Rhinorrhea

Interstitial lung

disease

Gastrointestinal

disorders

Diarrhea

Stomatitis

Nausea

Vomiting

Dyspepsia

Cheilitis

Pancreatitis

Gastrointestinal

perforation

Hepatobiliary

disorders

ALT increased

AST increased

Skin and

subcutaneous

tissue disorders

Rash

Dermatitis

acneiform

Pruritus

Dry skin

Nail disorders

Palmar-plantar

erythrodysesthesia

syndrome

Stevens-

Johnson

syndrome*

Toxic

epidermal

necrolysis*

Musculoskeletal

and connective

tissue disorders

Muscle spasms

Renal and urinary

disorders

Renal impairment

/renal failure

General disorders

and administration

site conditions

Pyrexia

Investigations

Weight decreased

* derived from post-marketing experience

Liver function test abnormalities

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

aspartate aminotransferase [AST]) were observed in patients receiving GIOTRIF 40 mg.

These elevations were mainly transient and did not lead to discontinuation of treatment.

Grade 2 (>2.5 to 5.0 times ULN [upper limit of normal]) ALT elevations occurred in 7.9% and

3.6% of patients treated with GIOTRIF or chemotherapy, respectively. Grade 3 (> 5.0 to 20.0

times ULN) elevations occurred in 3.5% and 1.8% of patients treated with GIOTRIF or

chemotherapy, respectively (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

GIOTRIF NZ DS v05

professionals

asked

report

suspected

adverse

reactions

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

4.9 Overdose

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

0800 764766.

Symptoms

The highest dose of GIOTRIF studied in a limited number of patients in Phase I clinical

trials was 160 mg once daily for 3 days and 100 mg once daily for 2 weeks. The adverse

reactions observed at this dose were primarily dermatological (rash/acne) and gastrointestinal

events (especially diarrhoea). Overdose in 2 healthy adolescents involving the ingestion of

360 mg each of GIOTRIF (as part of a mixed drug ingestion) was associated with adverse

drug reactions of nausea, vomiting, asthenia, dizziness, headache, abdominal pain and

elevated amylase (< 1.5 times ULN). Both subjects

recovered from these adverse events.

Treatment

There is no specific antidote for overdose with GIOTRIF. In cases of suspected overdose,

GIOTRIF should be withheld and supportive care instituted.

If indicated, elimination of unabsorbed afatinib may be achieved by emesis or gastric lavage.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents – protein kinase inhibitors, ATC

code: L01XE13.

Mechanism of action

Afatinib is an irreversible ErbB Family Blocker. Afatinib covalently binds to and irreversibly

blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR

(epidermal growth factor receptor, ErbB1), HER2 (human epidermal growth factor receptor 2,

ErbB2), ErbB3 and ErbB4.

Pharmacodynamic effects

Aberrant ErbB signalling triggered by, for instance, EGFR mutations and/or amplification,

HER2 amplification or mutation and/or ErbB ligand or receptor overexpression contributes to

the malignant phenotype in subsets of patients across multiple cancer types.

In nonclinical disease models with ErbB pathway deregulation, afatinib as a single agent

effectively blocks ErbB receptor signalling resulting in tumour growth inhibition or tumour

regression. Anti-tumour activity of afatinib was demonstrated in HER2 overexpressing models.

Various ErbB pathway aberrations (e.g. EGFR overexpression or mutation) were also the most

likely underlying cause for the activity of afatinib in lung cancer models. NSCLC models with

either L858R or Del 19 EGFR mutations are particularly sensitive to afatinib treatment.

In NSCLC, the acquisition of a secondary T790M mutation is a major mechanism of acquired

resistance to afatinib and gene dosage of the T790M-containing allele correlates with the

degree of resistance in vitro. The T790M mutation is found in approximately 50% of patients'

tumours upon disease progression on afatinib, for which T790M targeted EGFR TKIs may be

considered as a next line treatment option.

Cardiac Electrophysiology

GIOTRIF at doses of 50 mg daily did not result in significant prolongation of the QTcF

GIOTRIF NZ DS v05

interval after single and multiple administrations in patients with relapsed or refractory solid

tumours. There were no cardiac safety findings of clinical concern. This suggests that

GIOTRIF does not have a relevant effect on the QTcF interval.

Clinical efficacy and safety

GIOTRIF in EGFR mutation positive patients naïve to EGFR TKI treatment

LUX-Lung 3 (1200.32)

In the first-line setting, the efficacy and safety of GIOTRIF in patients with EGFR mutation-

positive locally advanced or metastatic NSCLC (stage IIIB or IV) were assessed in a

global, randomised, multicentre, open-label trial (LUX-Lung 3). Patients naïve to prior

systemic treatment for their advanced or metastatic disease were screened for the presence

of 29 different EGFR mutations using a polymerase chain reaction (PCR)-based method

(TheraScreen

: EGFR29 Mutation Kit, Qiagen Manchester Ltd). Patients (N=345) were

randomised (2:1) to receive GI

OTRIF 40 mg orally

once daily

(N=230) or up to 6 cycles

pemetrexed/cisplatin (N=115). Randomisation was stratified according to EGFR mutation

status (L858R; Del 19; other) and race (Asian; non-Asian). Dose escalation of GIOTRIF

to 50 mg was allowed after the first treatment cycle (21 days) if patients had no or limited

drug-related adverse events (i.e. absence of diarrhoea, skin rash, stomatitis, and/or other

drug-related events above Common

Terminology

Criteria

Adverse

Events

[CTCAE]

Grade 1), were compliant, and had no prior dose reduction.

In the overall trial population, the primary endpoint of progression free survival (PFS –

independent review, 221 events) showed a statistically significant improvement in PFS for

patients treated with GIOTRIF compared with patients treated with chemotherapy (median

PFS: 11.1 vs. 6.9 months HR 0.58, 95% CI

0.43-0.78;

p=0.0004). The percentages of

patients being alive and progression-free (PFS rate) at 12 months were 46.5% in patients

treated with GIOTRIF and 22% in patients treated with chemotherapy for the overall trial

population.

In the pre-defined sub-group of common mutations (L858R, Del 19) for GIOTRIF (N=204)

and chemotherapy (N=104) the median PFS was 13.6 months vs. 6.9 months respectively

(HR 0.47; 95% CI 0.34-0.65; p<0.0001). The PFS rate at 12 months was 51.1% in patients

treated with GIOTRIF and 21.4% in patients treated with chemotherapy and the median OS

was 30.3 months vs. 26.2 months (HR 0.82; 95% CI 0.59-1.14; p=0.2244). The Kaplan-

Meier curves for the primary PFS analysis in common mutations are shown in Figure 1.

GIOTRIF NZ DS v05

Figure 1: Kaplan-Meier Curves for PFS by independent review by treatment group in

LUX-Lung 3 for sub-group of common mutations (L858R, Del 19)

Of the 26 GIOTRIF-treated patients, eight achieved a partial response (N=4) or prolonged

disease control of longer than 6 months (N=4): 4 patients with mutations of the category

L858R+T790M (1 PR, PFS 11.0 months; 3 SD, 9.6+, 8.3, and 6.7 months); and 1 patient

in each with a mutation of the categories L861Q (1 SD, 8.3 months); G719X (1 PR, 10.8

months); S768I+L858R (1 PR, 13.8+ months); and S768I (1 PR, 19.2+ months). The PFS

was shorter than 6 months in all patients with the following mutation categories: T790M

alone (N=2), dele

tion 19 and T790M (N=3), G719X and T790M (N=1), exon 20 insertion

(n=6). There were 11 chemotherapy-treated patients in the “other” uncommon EGFR

mutation subgroup; of these, four (36%) achieved a partial response.

Efficacy results of trial LUX-Lung 3 are summarised in Table 4 below.

GIOTRIF NZ DS v05

Table 4:

Efficacy results of GIOTRIF vs. pemetrexed/cisplatin (LUX-Lung 3) based

on the primary PFS analysis as of 9 February 2012 (Independent review)

GIOTRIF

(N=230)

Pemetrexed / Cisplatin

(N=115)

Hazard Ratio

(HR)

/ Odds Ratio

(OR)

(95%

CI)

p-value

4

PFS, Overall Study Population

Months (median)

1-year PFS Rate

18-month PFS Rate

11.1

46.5%

26.4%

6.9

22.0%

8.6%

0.58

(0.43-0.78)

0.0004

PFS, Patients with L858R or Del 19

Mutations

1

Months (median)

1-year PFS Rate

18-month PFS Rate

13.6

51.1%

28.6%

6.9

21.4%

7.4%

0.47

(0.34-0.65)

<0.0001

Objective Response Rate

(CR+PR)

2

56.1%

22.6%

4.66

(2.77-7.83)

<0.0001

Disease Control Rate

(CR+PR+SD)

2

90.0%

80.9%

2.14

(1.13-4.04)

0.0189

Response D

uration

Months

(median)

11.1

5.5

Overall Survival (OS),

Overall Trial Population

Months (median)

28.2

28.2

HR 0.88

(0.66, 1.17)

0.39

N=308 (GIOTRIF: 204, pemetrexed/cisplatin: 104)

CR=complete response; PR=partial response; SD=stable disease

OS analysis as of December 2013

p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate and Disease Control

Rate based on logistic regression

The effect on PFS was consistent across major subgroups, including gender, age, race, ECOG

status, and mutation type (L858R, Del 19). There was no difference in overall survival (OS)

based on immature OS data with 28% deaths at the time of primary analysis (PFS). In the

predefined sub-group of common EGFR mutations (L858R, Del 19) for GIOTRIF (N=203) and

chemotherapy (N=104) the median OS was 31.6 months vs. 28.2 months (HR=0.78, 95% CI

(0.58, 1.06), p=0.1090. In the pre-defined EGFR mutation subgroups, the median OS with

first-line GIOTRIF vs. chemotherapy was 33.3 months vs. 21.1 months (HR = 0.54, (95% CI

0.36-0.79), p=0.0015) in patients with Del19 (n=169) and 27.6 months vs. 40.3 months (HR =

1.30, (95% CI: 0.80-2.11), p=0.2919) in patients with L858R (n=138).

benefit

GIOTRIF

accompanied

improvement

disease-related

symptoms, as measured by the European Organisation for Research and Treatment of

Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). In the overall

trial population, GIOTRIF significantly delayed the time to deterioration for the pre-specified

symptoms

cough

(HR 0.60; p=0.0072; median time not reached for GIOTRIF vs. 8.0

months for chemotherapy) and dyspnea (HR 0.68; p=0.0145; median time of 10.3 vs. 2.9

months). Significantly more patients treated with GIOTRIF compared with chemotherapy had

impro

vements for dyspnoea (64% vs. 50%; p=0.0103) and individual items of pain (‘Have

pain’: 56.0% vs. 40.0%; p=0.0095; ‘Pain in chest’: 51.0% vs. 37.0%; p=0.0184; ‘Pain in arm

or shoulder’: 41.0% vs. 26.0%; p=0.0103). For cough, numerically more patients improved

on GIOTRIF (67% vs. 60%; p=0.2444).

GIOTRIF NZ DS v05

LUX-Lung 6 (1200.34)

The efficacy and safety of GIOTRIF in Asian patients with EGFR mutation-positive locally

advanced or metastatic adenocarcinoma of the lung (stage IIIB/IV) was assessed in a

randomised, multicenter, open-label trial (LUX-Lung 6). Similar to LUX-Lung 3, patients naïve

to prior systemic treatment for their advanced or metastatic disease were screened for the

presence of 29 different EGFR mutations using a PCR based method (TheraScreen

EGFR29 Mutation Kit, Qiagen Manchester Ltd). Patients (N=364) were randomised (2:1) to

receive GIOTRIF 40 mg orally once daily (N=242) or up to 6 cycles gemcitabine/cisplatin

(N=122). Randomisation was stratified according to EGFR mutation status (L858R; Del 19;

other). Dose escalation of GIOTRIF to 50 mg was allowed after the first treatment cycle (21

days) if patients had no or limited drug-related adverse events (i.e. absence of diarrhoea, skin

rash, stomatitis, and/or other drug related events above CTCAE Grade 1), were compliant,

and had no prior dose reduction. Among randomised patients, 65% were female; the median

age was 58 years and all patients were Asian. Patients with common (L858R or Del 19) EGFR

mutations accounted for 89% of the study population.

The primary endpoint of PFS (central independent review, 221 events) showed a statistically

significant improvement in PFS for patients treated with GIOTRIF compared with patients

treated with chemotherapy (median PFS: 11.0 vs. 5.6 months). When comparing the

prespecified subgroup of common (L858R or Del 19) EGFR mutations, the difference in

median PFS remained constant (11.0 vs. 5.6 months). The percentages of patients being alive

and progression-free (PFS rate) at 12 months were 46.7% in patients treated with GIOTRIF

and 2.1% in patients treated with chemotherapy for the overall trial population, and 56.4% vs.

4.4% in the subgroup of common mutations.

The Kaplan-Meier curves of the primary PFS analysis are shown in Figure 2, and efficacy

results are summarised in Table 5. At the time of primary PFS analysis, a total of 57 (15.7%)

patients treated with GIOTRIF were known to be alive and progression-free and thus censored

in Figure 2.

GIOTRIF NZ DS v05

Figure 2:

Kaplan-Meier curves for PFS by independent review by treatment group

in LUX-Lung 6 Trial (Primary Analysis, Overall Population)

Table 5:

Efficacy results for GIOTRIF vs. gemcitabine/cisplatin (LUX-Lung 6 Trial)

based on the primary PFS analysis as of 29 October 2012 (Independent

review)

GIOTRIF

(N=242)

Gemcitabine/

Cisplatin

(N=122)

Hazard Ratio/

Odds Ratio

(95%CI)

p-value

4

PFS, Overall Trial

Population

Months (median)

1-year PFS Rate

18-months PFS Rate

11.0

46.7%

26.8%

5.6

2.1%

0.0%

HR 0.28

(0.20-0.39)

<0.0001

GIOTRIF NZ DS v05

GIOTRIF

(N=242)

Gemcitabine/

Cisplatin

(N=122)

Hazard Ratio/

Odds Ratio

(95%CI)

p-value

4

PFS, Patients with L858R

or Del 19 Mutations

1

Months (median)

1-year PFS Rate

18-months PFS Rate

11.0

56.4%

26.8%

5.6

4.4%

0.0%

HR 0.25

(0.18-0.35)

< 0.0001

Objective Response Rate

(CR+PR)

2

66.9%

23.0%

OR 7.28

(4.36-12.18)

< 0.0001

Disease Control Rate

(CR+PR+SD)

2

92.6%

76.2%

OR 3.84

(2.04-7.24)

<0.0001

Response Duration

Months (median)

9.7

4.3

Overall Survival (OS),

Overall Trial Population

Months (median)

23.1

23.5

HR 0.93

(0.72, 1.22)

0.6137

N=324 (GIOTRIF: 216, gemcitabine/cisplatin: 108)

CR=complete response; PR=partial response; SD=stable disease

Main OS analysis as of 27 December 2013 (when 246 patients had died)

p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response

Rate and Disease Control Rate based on logistic regression

The analysis of PFS based on investigator review yielded similar results (HR=0.26, CI= 95%

0.19–0.36; p<0.0001; median PFS: 13.7 vs. 5.6 months) as the analysis based on the

independent review. The effect on PFS was consistent across major subgroups, including

gender, age, race, ECOG status, and mutation type (L858R, Del 19) in both the independent

and investigator reviews. Based on investigator review, ORR was 74.4% vs. 31.1% and DCR

was 93.0% vs. 75.4% in GIOTRIF-treated patients compared with chemotherapy-treated

GIOTRIF NZ DS v05

patients. In the pre-defined subgroup of common EGFR mutations (Del 19, L858R) for

GIOTRIF (N=216) and chemotherapy (N=108) the median OS was 23.6 months vs. 23.5

months

(HR=0.83,

95% CI

(0.62-1.09),

p=0.1756).

pre-defined

EGFR

mutation

subgroups, the median OS with first-line GIOTRIF vs chemotherapy was 31.4 months vs 18.4

months (HR=0.64, (95% CI 0.44-0.94), p=0.0229) in patients with Del 19 (n=186) and 19.6

months vs 24.3 months (HR=1.22, (95% CI: 0.81-1.83), p=0.3432) in patients with L858R

(n=138).

The PFS benefit of GIOTRIF

was accompanied by improvement in disease-related symptoms,

as measured by the European Organization for Research and Treatment of Cancer (EORTC)

Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). GIOTRIF statistically significantly

delayed the time to deterioration for the pre-specified symptoms of cough (HR 0.453; 95% CI

0.299, 0.685; p = 0.0001), dyspnoea (HR 0.536; 95% CI 0.395, 0.727; p <0.0001), and pain

(HR 0.703; 95% CI 0.514, 0.961; p = 0.0265) compared with chemotherapy. Significantly more

patients treated with GIOTRIF compared with chemotherapy had improvements for cough

(75.9% of patients vs. 55.4%; p=0.0003), dyspnoea (70.9% vs. 47.5%; p <0.0001), and pain

(64.3% vs. 46.5%; p=0.0029).

Mean scores over time for health-related quality of life (HRQoL) were measured using the

EORTC QLQ-C30. Mean scores over time for overall quality of life, global health status and

physical, role, cognitive, social and emotional functioning were significantly favouring GIOTRIF

over chemotherapy.

LUX-Lung 2 (1200.22)

LUX-Lung 2 was an open label single arm Phase II trial which investigated the efficacy

and safety of GIOTRIF in 129 EGFR TKI-naïve patients with locally advanced or metastatic

lung adenocarcinoma (stage IIIB or IV) with EGFR mutations. Patients were enrolled in the

first-line (N=61) or second-line setting (N=68) (i.e. after failure of one prior chemotherapy

regimen). Patients were centrally screened for EGFR mutations. Patients received either 40

mg (N=30) or 50 mg (N=99) of GIOTRIF once daily.

The primary endpoint was ORR. Secondary endpoints included PFS, DCR and OS.

In 61 patients treated in the first-line setting, confirmed ORR was 65.6% and DCR was 86.9%

according to independent review. The median PFS was 12.0 months by independent review

and 15.6 months by investigator assessment. Median OS was not reached in the first-

line population. Efficacy was similarly high in the group of patients who had received prior

chemotherapy (N=68; ORR 57.4%; PFS by independent review 8 months and by investigator

assessment 10.5 months; DCR 77.9%). Median OS in the second line patients was 23.3

months (95% CI 18.5-38).

LUX-Lung 7 (1200.123)

LUX-Lung 7 is a randomised, global, open label Phase IIb trial investigating the efficacy and

safety of GIOTRIF in patients with locally advanced or metastatic lung adenocarcinoma (stage

IIIB or IV) with EGFR mutations in the first-line setting. Patients were screened for the

presence of activating EGFR mutations (Del 19 and/or L858R) using the TheraScreen

EGFR

RGQ PCR Kit, Qiagen Manchester Ltd). Patients (N=319) were randomised (1:1) to receive

GIOTRIF 40 mg orally once daily (N=160) or gefitinib 250 mg orally once daily (N=159).

Randomisation was stratified according to EGFR mutation status (Del 19; L858R) and

presence of brain metastases (yes; no).

GIOTRIF NZ DS v05

Among the patients randomised, 62% were female, the median age was 63 years, 16% of

patients had brain metastases, the baseline ECOG performance status was 0 (31%) or 1

(69%), 57% were Asian and 43% were non-Asian. Patients had a tumour sample with an

EGFR mutation categorised as either exon 19 deletion (58%) or exon 21 L858R substitutions

(42%).

The co-primary endpoints are PFS by independent review, time to treatment failure (TTF) and

OS. Secondary endpoints include ORR and DCR. The risk of progression was significantly

reduced for afatinib versus gefitinib (see Table 6) and ORR was 70% for afatinib and 56% for

gefitinib. Primary analysis of OS will be conducted after the number of required events has

occurred as per protocol.

Table 6:

Efficacy results of GIOTRIF vs. gefitinib (LUX-Lung 7 Trial) based on

primary analysis as of August 2015

GIOTRIF

(N=160)

Gefitinib

(N=159)

Hazard Ratio/

Odds Ratio

(95%CI)

p-value

2

Median PFS

(months), Overall

Trial Population

18-months PFS rate

24-months PFS rate

11.0

10.9

HR 0.73

(0.57-0.95)

0.0165

Time to Treatment

Failure (months)

18-months TTF rate

24-months TTF rate

13.7

11.5

HR 0.73

(0.58-0.92)

0.0073

Median OS

(months)

1

, Overall

Trial Population

27.9

25.0

HR 0.87

(0.65, 1.15)

0.33

OS analysis immature as of August 2015

p-value for PFS/ TTF/OS based on stratified log-rank test

The PFS hazard ratio for patients with DEL 19 mutations and L858R mutations was 0.76 (95%

CI [0.55, 1.06]; p=0.1071), and 0.71 (95% CI [0.47, 1.06]; p=0.0856) respectively for afatinib

vs gefitinib.

Analysis

of

GIOTRIF’s

efficacy

in

EGFR

TKI

naïve

patients

with

tumours

harbouring

uncommon EGFR Mutations (LUX-Lung 2, -3, and -6)

In three clinical trials of GIOTRIF with prospective tumour genotyping (Phase 3 trials LUX-

Lung 3 and – 6, and single arm Phase 2 trial LUX-Lung 2), an analysis was conducted of data

from a total of 75 TKI-naive patients with advanced (stage IIIb–IV) lung adenocarcinomas

harbouring uncommon EGFR mutations, which were defined as all mutations other than Del

19 and L858R mutations. Patients were treated with GIOTRIF 40 mg (all three trials) or 50 mg

(LUX-Lung 2) orally once daily.

In patients with tumours harbouring either G719X (N=18), L861Q (N=16), or S768I substitution

mutation (N=8), the confirmed ORR was 72.2%, 56.3%, 75.0%, respectively, and the median

duration of response was 13.2 months, 12.9 months and 26.3 months, respectively.

In patients with tumours harbouring exon 20 insertions (N=23) the confirmed ORR was 8.7%

and the median duration of response was 7.1 months. In patients with tumours harbouring de-

novo T790M mutations (N=14) the confirmed ORR was 14.3% and the median duration of

response was 8.3 months.

GIOTRIF NZ DS v05

GIOTRIF in patients with NSCLC of squamous histology

LUX-Lung 8 (1200.125)

The efficacy and safety of GIOTRIF as second-line treatment for patients with advanced

NSCLC of squamous histology was investigated in a randomised open-label global Phase III

trial LUX-Lung 8. Patients who received at least 4 cycles of platinum-based therapy in the first

line setting were subsequently randomised 1:1 to daily GIOTRIF 40 mg or erlotinib 150 mg

until progression. Dose escalation of GIOTRIF to 50 mg was allowed after first cycle (28 days)

on treatment in case of no or limited drug related adverse events (i.e. absence of diarrhoea,

skin rash, stomatitis, and/or other drug related events above CTCAE Grade 1), compliant

dosing and no prior dose reduction. Randomisation was stratified by race (Eastern Asian vs

non Eastern Asian). The primary endpoint was PFS (analysed when at least 372 events were

reported by independent review); OS was the key secondary endpoint (analysed at first 632

deaths). Other secondary endpoints included ORR, DCR, change in tumour size and HRQOL.

Among 795 patients randomised, the majority were males (83.8%), white (72.8%), current or

former smokers (91.6%) with baseline performance status ECOG 1 (66.8%).

Second-line GIOTRIF significantly improved PFS and OS of patients with squamous NSCLC

compared to erlotinib. In the primary PFS analysis median PFS was 2.43 months in the

GIOTRIF group and 1.94 months on erlotinib (HR=0.82, 95% CI (0.676, 0.998), p=0.0427).

The final PFS analysis including all randomised patients confirmed earlier results (Table 7).

The primary analysis of OS demonstrated significant reduction in the risk of death for patients

treated with GIOTRIF compared with erlotinib (HR=0.81 95% CI (0.69, 0.95), p=0.0077) with

significantly higher proportions of GIOTRIF-treated patients alive at the landmark points

throughout the period of observation such as 12 and 18 months post randomisation.

The rates of objective tumour response and stabilisation of disease were higher with GIOTRIF.

The median duration of response was 7.29 months on GIOTRIF and 3.71 months on erlotinib.

Table 7

Efficacy results for GIOTRIF vs erlotinib in LUX-Lung 8, based on

primary analysis of OS, including all randomised patients

GIOTRIF

(N=398)

Erlotinib

(n=397)

Hazard Ratio/

Odds Ratio

(95%CI)

p-value

1

PFS

Months (median)

2.63

1.94

HR 0.81

(0.69, 0.96)

0.0103

OS

Months (median)

Alive at 12 months

Alive at 18 months

7.92

36.4%

22.0%

6.77

28.2%

14.4%

HR 0.81

(0.69, 0.95)

0.0077

Objective Response

Rate (CR+PR)*

5.5%

2.8%

OR 2.06

(0.98, 4.32)

0.0551

Disease Control Rate

(CR+PR+SD)*

50.5%

39.5%

OR 1.56

(1.18, 2.06)

0.0020

*CR=complete response; PR=partial response; SD=stable disease

p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate and Disease Control

Rate based on logistic regression

GIOTRIF NZ DS v05

Figure 3:

Kaplan-Meier Curve for OS by treatment group in LUX Lung 8

analyses

patient

reported

outcomes,

based

on the QLQ-C30

and QLQ-LC13

questionnaires favoured GIOTRIF. Significantly more patients in the GIOTRIF group reported

improvement in the global health status/quality of life compared to erlotinib (35.7% vs 28.3%,

p=0.0406). Higher proportion of GIOTRIF patients had improvement in cough (43.4% vs

35.2%, p=0.0294) and dyspnoea (51.3% vs 44.1%, p=0.0605), while no difference was

observed for pain (40.2% vs 39.2%, p=0.7752). GIOTRIF significantly delayed the time to

deterioration of dyspnoea (HR 0.79, p=0.0078). Mean scores over time for cough, dyspnoea,

and pain as well as for physical, role, cognitive, and emotional functioning were significantly

better for GIOTRIF than for erlotinib.

5.2 Pharmacokinetic properties

Absorption

Following oral administration of GIOTRIF, maximum concentrations (C

) of afatinib are

observed approximately 2 to 5 hours post-dose. Mean C

and AUC

0-∞

values increased

slightly more than proportional in the dose range from 20 mg to 50 mg GIOTRIF. Systemic

exposure to afatinib is decreased by 50% (C

) and 39% (AUC

0-∞

), when administered with

a high-fat meal compared with administration in the fasted state.

Based on population

pharmacokinetic data derived from clinical trials in various tumour types, an average

decrease of 26% in AUC

τ,ss

was observed when food was consumed within 3 hours before or

1 hour after taking GIOTRIF. Therefore, food should not be consumed for at least 3 hours

before

at least

hour

after

taking

GIOTRIF (see sections

4.2 and 4.4). After

administration of GIOTRIF, the mean relative bioavailability was 92% (adjusted

gMean

ratio of AUC

0-∞

) when compared to an oral solution. The absolute bioavailability of

afatinib has not been determined.

Distribution

In vitro binding of afatinib to human plasma proteins is approximately 95%.

GIOTRIF NZ DS v05

Biotransformation

Enzyme-catalysed reactions play a minor role in the metabolism of afatinib in vivo. Covalent

adducts to proteins are the major circulating metabolites of afatinib. Approximately 2% of the

afatinib dose was metabolised by FMO3 and the CYP3A4-dependent N-demethylation was

too low to be quantitatively detected.

Elimination

Following administration of an oral solution of 15 mg afatinib, 85.4% of the dose was

recovered in the faeces and 4.3% in urine. The parent compound afatinib accounted for 88%

of the recovered dose. The apparent terminal half-life is 37 hours. Steady state plasma

concentrations of afatinib are achieved within 8 days of multiple dosing of afatinib resulting

in an accumulation of 2.77-fold (AUC) and 2.11-fold (C

Special populations

Renal impairment

Less than 5% of a single dose of afatinib is excreted via the kidneys. Exposure to afatinib in

subjects with renal impairment was compared to healthy volunteers following a single dose of

40 mg GIOTRIF. Subjects with moderate renal impairment (estimated glomerular filtration rate

[eGFR] of 30 to 59 mL/min/1.73m

according to MDRD formula) had an exposure of 101%

) and 122% (AUC

0-tz

) in comparison to their healthy controls. Subjects with severe renal

impairment (eGFR of 15 to 29 mL/min/1.73m

according to MDRD formula) had an exposure

of 122% (C

) and 150% (AUC

0-tz

) in comparison to their healthy controls. Based on this trial

and population pharmacokinetic analysis of data derived from clinical trials in various tumour

types it is concluded, that adjustments to the starting dose in patients with mild (eGFR 60-89

mL/min/1.73m

moderate

(eGFR

30-59

mL/min/1.73m

severe

(eGFR

15-29

mL/min/1.73m

) renal impairment are not necessary but patients with severe impairment

should be monitored (see “Population pharmacokinetic analysis in special populations” below

and section 4.2). GIOTRIF has not been studied in patients with eGFR <15 mL/min/1.73m

on dialysis.

Hepatic impairment

Afatinib is eliminated mainly by biliary/faecal excretion. Subjects with mild (Child Pugh A)

or moderate (Child Pugh B) hepatic impairment had similar exposure in comparison to healthy

volunteers following a single dose of 50 mg GIOTRIF. This is consistent with population

pharmacokinetic data derived from clinical trials in various tumour types (see Population

pharmacokinetic analysis in special populations below). No starting dose adjustments appear

necessary in patients with mild or moderate hepatic impairment (see section 4.2). The

pharmacokinetics of afat

inib had not been studied in subjects with severe (Child Pugh C)

hepatic dysfunction (see section 4.4).

Pharmacokinetic analysis in target populations

A population pharmacokinetic analysis was performed in 927 cancer patients (764 with

NSCLC) receiving GIOTRIF monotherapy. No starting dose adjustment is

considered

necessary for any of the following covariates tested.

Age

No significant impact of age (range: 28-87 years) on the pharmacokinetics of afatinib could be

observed.

Body weight

Plasma exposure (AUC

τ,ss

) was increased by 26% for a 42 kg patient (2.5th percentile)

and decreased by 22% for a 95 kg patient (97.5th percentile) relative to a patient weighing 62

kg (median body weight of patients in the overall patient population).

Gender

Female patients had a 15% higher plasma exposure (AUC

τ,ss

, body weight corrected) than

GIOTRIF NZ DS v05

male patients.

Race

There was no statistically significant difference in afatinib pharmacokinetics between Asian

and Caucasian patients. Also no obvious difference in pharmacokinetics for American

Indian/Alaska native or Black patients could be detected based on the limited data available

in these populations (6 and 9 out of 927 patients included in the analysis, respectively).

Renal impairment

Exposure to GIOTRIF moderately increased with lowering the creatinine clearance (CrCL),

i.e. for a patient with a CrCL of 60 or 30 mL/min exposure (AUC

τ,ss

) to afatinib increased

by 13% and 42%, respectively, and decreased by 6% and 20% for a patient with CrCL of

90 or 120 mL/min, respectively, compared to a patient with the CrCL of 79 mL/min (median

CrCL of patients in the overall patient population analysed).

Hepatic impairment

Patients with mild and moderate hepatic impairment as identified by abnormal liver tests did

not correlate with any significant change in afatinib exposure.

Other patient characteristics/intrinsic factors

Other patient characteristics/intrinsic factors found with a significant impact on afatinib

exposure

were:

ECOG

performance

score,

lactate

dehydrogenase

levels,

alkaline

phosphatase levels and total protein. The individual effect sizes of these covariates were

considered not clinically relevant.

Smoking history, alcohol consumption, or presence of liver metastases had no significant

impact on the pharmacokinetics of afatinib.

Pharmacokinetic Drug Interactions

Drug transporters:

P-glycoprotein (P-gp)

Effect of P-gp inhibitors and inducers on afatinib: Two trials were conducted to assess the

effect of ritonavir, a potent inhibitor of P-gp, on the pharmacokinetics of afatinib. In one trial,

the relative bioavailability of afatinib was investigated when ritonavir (200 mg b.i.d. for 3

days) was given either simultaneously or 6 hours after a single dose of 40 mg GIOTRIF.

relative

bioavailability

afatinib

119%

(AUC

0-∞

104%

when

administered

simultaneously

with ritonavir

111%

(AUC

0-∞

and 105% (C

) when

ritonavir was administer

ed 6 hours after GIOTRIF. In a second trial, when ritonavir

(200 mg

b.i.d. for 3 days) was administered 1 hour before a single dose of 20 mg GIOTRIF,

exposure to afatinib increased by 48% (AUC

0-∞

) and 39% (C

) (see sections 4.4, 4.5 and

4.2).

Pre-treatment with rifampicin (600 mg q.d. for 7 days), a potent inducer of P-gp, decreased

the plasma exposure to afatinib by 34% (AUC

0-∞

) and 22% (C

) after administration of a

single dose of 40 mg GIOTRIF (see sections 4.4 and 4.5).

Effect of afatinib on P-gp Substrates: Based on in vitro data, afatinib is a moderate inhibitor of

P-gp. However, based on clinical data it is considered unlikely that GIOTRIF treatment will

result in changes of the plasma concentrations of other P-gp substrates.

Breast cancer resistance protein (BCRP)

In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP.

Drug Uptake Transport Systems

GIOTRIF NZ DS v05

In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATB1B1,

OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transporters are considered

unlikely.

Drug Metabolising Enzymes:

Cytochrome P450 (CYP) enzymes

Effect of CYP enzymes inducers and inhibitors on afatinib: In vitro data indicated that drug-

drug interactions with afatinib due to inhibition or induction of CYP enzymes by concomitant

medicines are considered unlikely. In humans it was found that enzyme-catalysed metabolic

reactions play a negligible role in the metabolism of afatinib. Approximately 2% of the afatinib

dose was metabolised by FMO3 and the CYP3A4-dependent N-demethylation was too low to

be quantitatively detected.

Effect of afatinib on CYP enzymes: Afatinib is neither an inhibitor or an inducer of CYP

enzymes. Therefore, GIOTRIF is unlikely to affect the metabolism of other medicines that are

dependent on CYP enzymes.

UDP-glucuronosyltransferase 1A1 (UGT1A1)

In vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 are

considered unlikely.

5.3 Preclinical safety data

Oral administration of single doses to mice and rats indicated a low acute toxic potential of

afatinib. In oral repeated-dose studies for up to 26 weeks in rats or 52 weeks in minipigs

the main effects were identified in the skin (dermal changes, epithelial atrophy and

folliculitis in rats), the gastrointestinal tract (diarrhoea, erosions in the stomach, epithelial

atrophy in rats and minipigs) and the kidneys (papillary necrosis in rats). Depending on the

finding, these changes occurred at exposures below, in the range of or above clinically

relevant levels. Additionally, in various organs pharmacodynamically mediated atrophy of

epithelia was observed in both species.

Reproduction toxicity

Based on the mechanism of action, all EGFR targeting medicinal products including

GIOTRIF have the potential to cause foetal harm. The embryo-foetal development studies

performed on afatinib revealed no indication of teratogenicity. The respective total systemic

exposure (AUC) was either slightly above (2.2 times in rats) or below (0.3 times in rabbits)

compared with levels in patients.

Radiolabelled afatinib administered orally to rats on Day 11 of lactation was excreted in the

breast milk of the dams.

A fertility study in male and female rats up to the maximum tolerated dose revealed no

significant impact on fertility. The total systemic exposure (AUC

0-24

) in male and female rats

was in the range or less than that observed in patients (1.3 times and 0.51 times,

respectively). A study in rats up to the maximum tolerated doses revealed no significant

impact on pre-/postnatal development. The highest total systemic exposure (AUC

0-24

) in

female rats was less than that observed in patients (0.23 times).

Phototoxicity

An in vitro mouse 3T3 cell phototoxicity test with afatinib was performed. It was concluded

that GIOTRIF may have phototoxicity potential.

GIOTRIF NZ DS v05

Carcinogenicity

Carcinogenicity studies have not been conducted with afatinib.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core

lactose monohydrate

microcrystalline cellulose

colloidal silicon dioxide

crospovidone

magnesium stearate.

Film coating

GIOTRIF 20 mg film-coated tablets

hypromellose

macrogol 400

titanium dioxide

purified talc

polysorbate 80

GIOTRIF 30, 40 and 50 mg film-coated tablets

hypromellose

macrogol 400

titanium dioxide

purified talc

polysorbate 80

Indigo carmine aluminium lake

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store below 30°C.

Store in the original package in order to protect from moisture and light.

6.5 Nature and contents of container

PVC/PVDC perforated unit dose blister. Each blister is packed together with a desiccant

sachet in a laminated aluminium pouch and contains 7 x 1 film-coated tablets. Pack sizes of

7 x 1, 14 x 1 or 28 x 1 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with

local requirements.

GIOTRIF NZ DS v05

7. MEDICINE SCHEDULE

Prescription Medicine

8. SPONSOR

Boehringer Ingelheim (N.Z.) Limited

P.O. Box 76-216

Manukau City

Auckland

NEW ZEALAND

Telephone

0800 802 461

9. DATE OF FIRST APPROVAL

6 November 2014

10. DATE OF REVISION OF THE TEXT

18 January 2021

SUMMARY TABLE OF CHANGES

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