Erlotinib Orion 100 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

29-01-2020

Produktens egenskaper Produktens egenskaper (SPC)

29-01-2020

Aktiva substanser:
erlotinibhydroklorid
Tillgänglig från:
Orion Corporation
ATC-kod:
L01EB02
INN (International namn):
erlotinib hydrochloride
Dos:
100 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
erlotinibhydroklorid 109,3 mg Aktiv substans; laktos (vattenfri) Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 30 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
57349
Tillstånd datum:
2019-01-15

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

29-01-2019

Produktens egenskaper Produktens egenskaper - engelska

15-03-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

06-03-2019

Läs hela dokumentet

Package leaflet: Information for the user

Erlotinib Orion 25 mg film-coated tablets

Erlotinib Orion 100 mg film-coated tablets

Erlotinib Orion 150 mg film-coated tablets

Erlotinib

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Erlotinib Orion is and what it is used for

What you need to know before you take Erlotinib Orion

How to take Erlotinib Orion

Possible side effects

How to store Erlotinib Orion

Contents of the pack and other information

1.

What Erlotinib Orion is and what it is used for

Erlotinib Orion contains the active substance erlotinib. Erlotinib Orion is a medicine used to treat cancer by

preventing the activity of a protein called epidermal growth factor receptor (EGFR). This protein is known to

be involved in the growth and spread of cancer cells.

Erlotinib Orion is indicated for adults. This medicine can be prescribed to you if you have non-small cell

lung cancer at an advanced stage. It can be prescribed as initial therapy or as therapy if your disease remains

largely unchanged after initial chemotherapy, provided your cancer cells have specific EGFR mutations. It

can also be prescribed if previous chemotherapy has not helped to stop your disease.

This medicine can also be prescribed to you in combination with another treatment called gemcitabine if you

have cancer of the pancreas at a metastatic stage.

2.

What you need to know before you take

Erlotinib Orion

Do not take Erlotinib Orion:

if you are allergic to erlotinib or any of the ingredients of this medicine (listed in section 6).

Warnings and precautions

if you are taking other medicines that may increase or decrease the amount of erlotinib in your blood or

influence its effect (for example antifungals like ketoconazole, protease inhibitors, erythromycin,

clarithromycin, phenytoin, carbamazepine, barbiturates, rifampicin, ciprofloxacin, omeprazole,

ranitidine, St. John’s Wort or proteasome inhibitors), talk to your doctor. In some cases these medicines

may reduce the efficacy or increase the side effects of Erlotinib Orion and your doctor may need to

adjust your treatment. Your doctor might avoid treating you with these medicines while you are

receiving Erlotinib Orion.

if you are taking anticoagulants (a medicine which helps to prevent thrombosis or blood clotting e.g.

warfarin), Erlotinib Orion may increase your tendency to bleed. Talk to your doctor, he will need to

regularly monitor you with some blood tests.

if you are taking statins (medicines to lower your blood cholesterol), Erlotinib Orion may increase the

risk of statin related muscle problems, which on rare occasions can lead to serious muscle breakdown

(rhabdomyolysis) resulting in kidney damage, talk to your doctor.

if you 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, tell your doctor.

See also below “Other medicines and Erlotinib Orion”

You should tell your doctor:

if you have sudden difficulty in breathing associated with cough or fever because your doctor may need

to treat you with other medicines and interrupt your Erlotinib Orion treatment

if you have diarrhoea because your doctor may need to treat you with anti-diarrhoeal (for example

loperamide)

immediately, if you have severe or persistent diarrhoea, nausea, loss of appetite, or vomiting because

your doctor may need to interrupt your Erlotinib Orion treatment and may need to treat you in the

hospital

if you have severe pain in the abdomen, severe blistering or peeling of skin. Your doctor may need to

interrupt or stop your treatment

if you develop acute or worsening redness and pain in the eye, increased eye watering, blurred vision

and/or sensitivity to light, please tell your doctor or nurse immediately as you may need urgent

treatment (see Possible Side Effects below)

if you are also taking a statin and experience unexplained muscle pain, tenderness, weakness or cramps.

Your doctor may need to interrupt or stop your treatment.

See also section 4 “Possible side effects”.

Liver or kidney disease

It is not known whether Erlotinib Orion has a different effect if your liver or kidneys are not functioning

normally. The treatment with this medicine is not recommended if you have a severe liver disease or severe

kidney disease.

Glucuronidation disorder like Gilbert’s syndrome

Your doctor must treat you with caution if you have a glucuronidation disorder like Gilbert’s syndrome.

Smoking

You are advised to stop smoking if you are treated with Erlotinib Orion as smoking could decrease the

amount of your medicine in the blood.

Children and adolescents

Erlotinib Orion has not been studied in patients under the age of 18 years. The treatment with this medicine

is not recommended for children and adolescents.

Other medicines and Erlotinib Orion

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Erlotinib Orion with food and drink

Do not take Erlotinib Orion with food. See also section 3 ‘How to take Erlotinib Orion’.

Pregnancy and breast-feeding

Avoid pregnancy while being treated with Erlotinib Orion. If you 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 Orion, immediately inform your doctor

who will decide if the treatment should be continued.

Do not breast-feed if you are being treated with Erlotinib Orion, and for at least 2 weeks after taking the last

tablet.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Erlotinib Orion has not been studied for its possible effects on the ability to drive and use machines but it is

very unlikely that your treatment will affect this ability.

Erlotinib Orion contains lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before

taking this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

3.

How to take Erlotinib Orion

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you

are not sure.

The tablet should be taken at least one hour before or two hours after the ingestion of food.

The recommended dose is one tablet of Erlotinib Orion 150 mg each day if you have non-small cell lung

cancer.

The recommended dose is one tablet of Erlotinib Orion 100 mg each day if you have metastatic pancreatic

cancer. Erlotinib Orion is given in combination with gemcitabine treatment.

Your doctor may adjust your dose in 50 mg steps. For the different dose regimens Erlotinib Orion is

available in strengths of 25 mg, 100mg or 150 mg.

If you take more Erlotinib Orion than you should

Contact your doctor or pharmacist immediately. You may have increased side effects and your doctor may

interrupt your treatment.

If you forget to take Erlotinib Orion

If you miss one or more doses of Erlotinib Orion, contact your doctor or pharmacist as soon as possible. Do

not take a double dose to make up for a forgotten dose.

If you stop taking Erlotinib Orion

It is important to keep taking Erlotinib Orion every day, as long as your doctor prescribes it for you.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact your doctor as soon as possible if you suffer from any of the below side effects. In some cases

your doctor may need to reduce your dose of Erlotinib Orion or interrupt treatment:

Diarrhoea and vomiting (very common: may affect more than 1 out of 10 people). Persistent and

severe diarrhoea may lead to low blood potassium and impairment of your kidney function,

particularly if you receive other chemotherapy treatments at the same time. If you experience more

severe or persistent diarrhoea contact your doctor immediately as your doctor may need to treat you

in the hospital.

Eye irritation due to conjunctivitis/keratoconjunctivitis (very common: may affect more than 1 out of

10 people) and keratitis (common: may affect up to 1 in 10 people).

Form of lung irritation called interstitial lung disease (uncommon in European patients; common in

Japanese patients: may affect up to 1 in 100 people in Europe and up to 1 in 10 in Japan). This

disease can also be linked to the natural progression of your medical condition and can have a fatal

outcome in some cases. If you develop symptoms such as sudden difficulty in breathing associated

with cough or fever contact your doctor immediately as you could suffer from this disease. Your

doctor may decide to permanently stop your treatment with Erlotinib Orion.

Gastrointestinal perforations have been observed (uncommon: may affect up to 1 in 100 people).

Tell your doctor if you have severe pain in your abdomen. Also, tell your doctor if you had peptic

ulcers or diverticular disease in the past, as this may increase this risk.

In rare cases liver failure was observed (rare: may affect up to 1 in 1,000 people). If your blood tests

indicate severe changes in your liver function, your doctor may need to interrupt your treatment.

Very common side effects (may affect more than 1 in 10 people):

Rash which may occur or worsen in sun exposed areas. If you are exposed to sun, protective

clothing, and/or use of sun screen (e.g. mineral-containing) may be advisable

Infection

Loss of appetite, decreased weight

Depression

Headache, altered skin sensation or numbness in the extremities

Difficulty in breathing, cough

Nausea

Mouth irritation

Stomach pain, indigestion and flatulence

Abnormal blood tests for the liver function

Itching, dry skin and loss of hair

Tiredness, fever, rigors.

Common side effects (may affect up to 1 in 10 people):

Bleeding from the nose

Bleeding from the stomach or the intestines

Inflammatory reactions around the fingernail

Infection of hair follicles

Acne

Cracked skin (skin fissures)

Reduced kidney function (when given outside the approved indications in combination with

chemotherapy).

Uncommon side effects (may affect up to 1 in 100 people):

Eyelash changes

Excess body and facial hair of a male distribution pattern

Eyebrow changes

Brittle and loose nails.

Rare side effects (may affect up to 1 in 1,000 people):

Flushed or painful palms or soles (Palmar plantar erythrodysaesthesia syndrome).

Very rare side effects (may affect up to 1 in 10,000 people):

Cases of perforation or ulceration of the cornea

Severe blistering or peeling of skin (suggestive of Stevens-Johnson syndrome)

Inflammation of the coloured part of the eye.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed

in this leaflet.

You can also report side effects directly via the national reporting system listed in Appendix

V. By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Erlotinib Orion

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry

date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Erlotinib Orion contains

The active substance is erlotinib. Each tablet contains erlotinib hydrochloride equivalent to 25 mg,

100 mg or 150 mg of erlotinib.

The other ingredients are:

Tablet core:

lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal

anhydrous silica (see section 2 ‘Erlotinib Orion contains lactose and sodium’).

Tablet coat:

hypromellose, hydroxypropylcellulose, triethyl citrate, titanium dioxide (E171).

What Erlotinib Orion looks like and contents of the pack

25 mg:

White to off-white, round, biconvex coated tablet, diameter 5.6 mm. Engraved “ER” over “25” on

one side, “APO” on the other side.

100 mg:

White to off-white, round, biconvex coated tablet, diameter 8.7 mm. Engraved “ER” over “100” on

one side, “APO” on the other side.

150 mg:

White to off-white, round, biconvex coated tablet, diameter 10.3 mm. Engraved “ER” over “150” on

one side, “APO” on the other side.

Erlotinib Orion are available in blister pack of 30 tablets.

Marketing Authorisation Holder

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

Manufacturers

Orion Corporation Orion Pharma

Orionintie 1

FI-02200 Espoo

Finland

Orion Corporation Orion Pharma

Joensuunkatu 7

FI-24100 Salo

Finland

This leaflet was last revised on

2019-12-20

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Erlotinib Orion 25 mg film-coated tablets

Erlotinib Orion 100 mg film-coated tablets

Erlotinib Orion 150 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Erlotinib Orion 25 mg film-coated tablets

Each tablet contains erlotinib hydrochloride equivalent to 25 mg of erlotinib.

Erlotinib Orion 100 mg film-coated tablets

Each tablet contains erlotinib hydrochloride equivalent to 100 mg of erlotinib.

Erlotinib Orion 150 mg film-coated tablets

Each tablet contains erlotinib hydrochloride equivalent to 150 mg of erlotinib.

Excipient(s) with known effect:

Each 25 mg film-coated tablet contains 29 mg lactose and 0.34 mg sodium.

Each 100 mg film-coated tablet contains 115 mg lactose and 1.4 mg sodium.

Each 150 mg film-coated tablet contains 173 mg lactose and 2.1 mg sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

25 mg: White to off-white, round, biconvex coated tablet, diameter 5.6 mm. Engraved “ER” over “25” on

one side, “APO” on the other side.

100 mg: White to off-white, round, biconvex coated tablet, diameter 8.7 mm. Engraved “ER” over “100”

on one side, “APO” on the other side.

150 mg: White to off-white, round, biconvex coated tablet, diameter 10.3 mm. Engraved “ER” over

“150” on one side, “APO” on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Non-Small Cell Lung Cancer (NSCLC):

Erlotinib Orion is indicated for the first-line treatment of patients with locally advanced or metastatic non-

small cell lung cancer (NSCLC) with EGFR activating mutations.

Erlotinib Orion is also indicated for switch maintenance treatment in patients with locally advanced or

metastatic NSCLC with EGFR activating mutations and stable disease after first-line chemotherapy.

Erlotinib Orion is also indicated for the treatment of patients with locally advanced or metastatic NSCLC

after failure of at least one prior chemotherapy regimen. In patients with tumours without EGFR

activating mutations, Erlotinib Orion is indicated when other treatment options are not considered

suitable.

When prescribing Erlotinib Orion, factors associated with prolonged survival should be taken into

account.

No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients

with Epidermal Growth Factor Receptor (EGFR)-IHC negative tumours (see section 5.1).

Pancreatic cancer:

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

pancreatic cancer.

When prescribing Erlotinib Orion, factors associated with prolonged survival should be taken into

account (see sections 4.2 and 5.1).

No survival advantage could be shown for patients with locally advanced disease.

4.2 Posology and method of administration

Posology

Erlotinib Orion treatment should be supervised by a physician experienced in the use of anti-cancer

therapies.

Patients with Non-Small Cell Lung Cancer:

EGFR mutation testing should be performed in accordance with the approved indications (see section

4.1).

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

after the ingestion of food.

Patients with pancreatic cancer:

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

after the ingestion of food, in combination with gemcitabine (see the summary of product characteristics

of gemcitabine for the pancreatic cancer indication). In patients who do not develop rash within the first

4 – 8 weeks of treatment, further Erlotinib Orion treatment should be re-assessed (see section 5.1).

When dose adjustment is necessary, the dose should be reduced in 50 mg steps (see section 4.4).

Erlotinib Orion is available in strengths of 25 mg, 100 mg and 150 mg.

Concomitant use of CYP3A4 substrates and modulators may require dose adjustment (see section 4.5).

Hepatic impairment

Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was

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

patients with adequate hepatic function, caution should be used when administering Erlotinib Orion to

patients with hepatic impairment. Dose reduction or interruption of Erlotinib Orion should be considered

if severe adverse reactions occur. The safety and efficacy of erlotinib has not been studied in patients with

severe hepatic dysfunction (AST/SGOT and ALT/SGPT> 5 x ULN). Use of Erlotinib Orion in patients

with severe hepatic dysfunction is not recommended (see section 5.2).

Renal impairment

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

creatinine concentration >1.5 times the upper normal limit). Based on pharmacokinetic data no dose

adjustments appear necessary in patients with mild or moderate renal impairment (see section 5.2). Use of

Erlotinib Orion in patients with severe renal impairment is not recommended.

Paediatric population

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

Erlotinib Orion in paediatric patients is not recommended.

Smokers

Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerated dose

of erlotinib in NSCLC patients who currently smoke cigarettes was 300 mg. The 300 mg dose didn’t

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. Safety data were comparable

between the 300 mg and 150 mg doses; however, there was a numerical increase in the incidence of rash,

interstitial lung disease and diarrhoea, in patients receiving the higher dose of erlotinib. Current smokers

should be advised to stop smoking (see sections 4.4, 4.5, 5.1 and 5.2).

Method of administration

Oral use.

4.3 Contraindications

Hypersensitivity to erlotinib 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 considering the use of Erlotinib Orion as a first line or maintenance treatment for locally advanced

or metastatic NSCLC, it is important that the EGFR mutation status of a patient is determined.

A validated, robust, reliable and sensitive test with a prespecified positivity threshold and demonstrated

utility for the determination of EGFR mutation status, using either tumor DNA derived from a tissue

sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be performed

according to local medical practice.

If a plasma-based cfDNA test is used and the result is negative for activating mutations, perform a tissue

test wherever possible due to the potential for false negative results from a plasma-based test.

Smokers

Current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as

compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant (see

sections 4.2, 4.5, 5.1 and 5.2).

Interstitial Lung Disease

Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly

in patients receiving erlotinib for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or

other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was the

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

clinical trials (excluding phase I and single-arm phase II studies due to lack of control groups), 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.

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 (ARDS), alveolitis, and lung

infiltration. Symptoms started from a few days to several months after initiating erlotinib therapy.

Confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-

existing parenchymal lung disease, metastatic lung disease, or pulmonary infections were frequent. A

higher incidence of ILD (approximately 5% with a mortality rate of 1.5%) is seen among patients in

studies conducted in Japan.

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. Patients

treated concurrently with erlotinib and gemcitabine should be monitored carefully for the possibility to

develop ILD-like toxicity. If ILD is diagnosed, erlotinib should be discontinued and appropriate treatment

initiated as necessary (see section 4.8).

Diarrhoea, dehydration, electrolyte imbalance and renal failure

Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50% of patients

on erlotinib and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose

reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions

by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea,

anorexia, or vomiting associated with dehydration, erlotinib therapy should be interrupted and appropriate

measures should be taken to treat the dehydration (see section 4.8). There have been rare reports of

hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration

due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy.

In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of

patients with aggravating risk factors (especially concomitant chemotherapy and other 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.

Hepatitis, hepatic failure

Rare cases of hepatic failure (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 dosing should be interrupted

if changes in liver function are severe (see section 4.8). Erlotinib is not recommended for use in patients

with severe hepatic dysfunction.

Gastrointestinal perforation

Patients receiving erlotinib are at 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 be permanently

discontinued in patients who develop gastrointestinal perforation (see section 4.8).

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). Erlotinib treatment should be interrupted or discontinued if the patient develops severe

bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disorders should be

tested for skin infection and treated according to local management guidelines.

Ocular disorders

Patients presenting with signs and symptoms suggestive of keratitis 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

erlotinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of

continuing treatment should be carefully considered. Erlotinib should be used with caution in patients

with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for

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

of erlotinib (see section 4.8).

Interactions with other medicinal products

Potent inducers of CYP3A4 may reduce the efficacy of erlotinib whereas potent inhibitors of CYP3A4

may lead to increased toxicity. Concomitant treatment with these types of agents should be avoided (see

section 4.5).

Other forms of interactions

Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH

of the upper Gastro-Intestinal (GI) tract, like proton pump inhibitors, H2 antagonists and antacids, may

alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of erlotinib when co-

administered with such agents is not likely to compensate for the loss of exposure. Combination of

erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of

erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely.

Therefore, concomitant administration of these combinations should be avoided (see section 4.5). If the

use of antacids is considered necessary during treatment with erlotinib, they should be taken at least 4

hours before or 2 hours after the daily dose of erlotinib.

Erlotinib Orion tablets contain lactose and sodium. Patients with rare hereditary problems of galactose

intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Erlotinib and other CYP substrates

Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as

a strong inhibitor of glucuronidation by UGT1A1

in vitro

The physiological relevance of the strong inhibition of CYP1A1 is unknown due to the very limited

expression of CYP1A1 in human tissues.

When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib

exposure [AUC] increased significantly by 39%, while no statistically significant change in C

found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and

, respectively. The clinical relevance of this increase has not been established. Caution should be

exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with

erlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.

Pre-treatment or co-administration of erlotinib did not alter the clearance of the prototypical CYP3A4

substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam

by up to 24%. In another clinical study, erlotinib was shown not to affect pharmacokinetics of the

concomitantly administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with the clearance

of other CYP3A4 substrates are therefore unlikely.

The inhibition of glucuronidation may cause interactions with medicinal products which are substrates of

UGT1A1 and exclusively cleared by this pathway. Patients with low expression levels of UGT1A1 or

genetic glucuronidation disorders (e.g. Gilbert’s disease) may exhibit increased serum concentrations of

bilirubin and must be treated with caution.

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a

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

CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential

interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of,

these enzymes.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma

concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally

twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase of erlotinib exposure (86% of

AUC and 69% of C

). Therefore, caution should be used when erlotinib is combined with a potent

CYP3A4 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole, voriconazole), protease

inhibitors, erythromycin or clarithromycin. If necessary the dose of erlotinib should be reduced,

particularly if toxicity is observed.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib

plasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally

once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% decrease in the median erlotinib

AUC. Co-administration of rifampicin with a single 450 mg dose of erlotinib resulted in a mean erlotinib

exposure (AUC) of 57.5% of that after a single 150 mg erlotinib dose in the absence of rifampicin

treatment. Co-administration of erlotinib with CYP3A4 inducers should therefore be avoided. 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 (including renal and liver functions

and serum electrolytes) is closely monitored, and if well tolerated for more than 2 weeks, further increase

to 450 mg could be considered with close safety monitoring. Reduced exposure may also occur with other

inducers e.g. phenytoin, carbamazepine, barbiturates or St. John’s Wort (

hypericum perforatum

). Caution

should be observed when these active substances are combined with erlotinib. Alternate treatments

lacking potent CYP3A4 inducing activity should be considered when possible.

Erlotinib and coumarin-derived anticoagulants

Interaction with coumarin-derived anticoagulants including warfarin leading to increased International

Normalized Ratio (INR), and bleeding events, which in some cases were fatal, have been reported in

patients receiving erlotinib. Patients taking coumarin-derived anticoagulants should be monitored

regularly for any changes in prothrombin time or INR.

Erlotinib and statins

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

including rhabdomyolysis, which was observed rarely.

Erlotinib and smokers

Results of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced

and plasma concentration at 24 hours, respectively, after administration of erlotinib in

smokers as compared to non-smokers. Therefore, patients who are still smoking should be encouraged to

stop smoking as early as possible before initiation of treatment with erlotinib, as plasma erlotinib

concentrations are reduced otherwise. Based on the data from the CURRENTS study, no evidence was

seen for any benefit of a higher erlotinib dose of 300 mg when compared with the recommended dose of

150 mg in active smokers. Safety data were comparable between the 300 mg and 150 mg doses; however,

there was a numerical increase in the incidence of rash, interstitial lung disease and diarrhoea, in patients

receiving the higher dose of erlotinib (see sections 4.2, 4.4, 5.1 and 5.2).

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate for the P-glycoprotein active substance transporter. Concomitant administration of

inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or altered

elimination of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not been

established. Caution should be exercised in such situations.

Erlotinib and medicinal products altering pH

Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH

of the upper Gastro-Intestinal (GI) tract may alter the solubility of erlotinib and hence its bioavailability.

Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib

exposure [AUC] and maximum concentration [C

] by 46% and 61%, respectively. There was no change

to T

or half-life. Concomitant administration of erlotinib with 300 mg ranitidine, an H2-receptor

antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [C

] by 33% and 54%,

respectively. Increasing the dose of erlotinib when co-administered with such agents is not likely to

compensate for this loss of exposure. However, when erlotinib was dosed in a staggered manner 2 hours

before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and maximum concentrations

] decreased only by 15% and 17%, respectively. The effect of antacids on the absorption of erlotinib

has not been investigated but absorption may be impaired, leading to lower plasma levels. In summary,

the combination of erlotinib with proton pump inhibitors should be avoided. If the use of antacids is

considered necessary during treatment with erlotinib, they should be taken at least 4 hours before or 2

hours after the daily dose of erlotinib. If the use of ranitidine is considered, it should be used in a

staggered manner; i.e. erlotinib must be taken at least 2 hours before or 10 hours after ranitidine dosing.

Erlotinib and gemcitabine

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

nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.

Erlotinib and carboplatin/paclitaxel

Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with

carboplatin and paclitaxel led to an increase of total platinum AUC

0-48

of 10.6%. Although statistically

significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice,

there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There

were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.

Erlotinib and capecitabine

Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination with

capecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in

when compared with values observed in another study in which erlotinib was given as single agent.

There were no significant effects of erlotinib on the pharmacokinetics of capecitabine.

Erlotinib and proteasome inhibitors

Due to the working mechanism, proteasome inhibitors including bortezomib may be expected to

influence the effect of EGFR inhibitors including erlotinib. Such influence is supported by limited clinical

data and preclinical studies showing EGFR degradation through the proteasome.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shown no

evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy can not

be excluded as rat and rabbit studies have shown increased embryo/foetal lethality (see section 5.3). The

potential risk for humans is unknown.

Women of childbearing potential

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

Breast-feeding

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 breast-feeding while receiving Erlotinib

Orion and for at least 2 weeks after the final dose.

Fertility

Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the

fertility can not be excluded as animal studies have shown effects on reproductive parameters (see section

5.3). The potential risk for humans is unknown.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed; however erlotinib

is not associated with impairment of mental ability.

4.8 Undesirable 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 or 150 mg

in combination with gemcitabine.

The incidence of adverse drug reactions (ADRs) from clinical trials reported with erlotinib alone or in

combination with chemotherapy are summarised by National Cancer Institute-Common Toxicity Criteria

(NCI-CTC) grade in Table 1. The listed ADRs 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. Other ADRs including those from other studies are summarised in Table 2.

Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. The

corresponding frequency category for each adverse drug reaction is based on the following convention:

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), very rare (<1/10,000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Non-small cell lung cancer (erlotinib administered as monotherapy):

First-Line Treatment of Patients with EGFR Mutations

In an open-label, randomised phase III study, ML20650 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 ADRs seen in patients treated with erlotinib in study ML20650 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.

Maintenance treatment

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

BO25460 (IUNO); erlotinib was administered as maintenance after first-line chemotherapy. These studies

were 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.

The most frequent ADRs seen in patients treated with erlotinib in studies BO18192 and BO25460 were

rash (BO18192: all grades 49.2%, grade 3: 6.0%; BO25460: all grades 39.4%, grade 3: 5.0%) and

diarrhoea (BO18192: all grades 20.3%, grade 3: 1.8%; BO25460: all grades 24.2%, grade 3: 2.5%). No

grade 4 rash or diarrhoea was observed in either study. Rash and diarrhoea resulted in discontinuation of

erlotinib in 1% and <1% of patients, respectively, in study BO18192, while no patients 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.

Second and Further Line Treatment

In a randomised double-blind study (BR.21; erlotinib administered as second line therapy), rash (75%)

and diarrhoea (54%) were the most commonly reported adverse drug reactions (ADRs). Most were grade

1/2 in severity and manageable without intervention. Grade 3/4 rash and diarrhoea occurred in 9% and

6%, respectively in erlotinib treated patients and each resulted in study discontinuation in 1% of patients.

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.

In general, rash 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 (e.g. mineral-containing) may be advisable.

Pancreatic cancer (erlotinib administered concurrently with gemcitabine):

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

erlotinib 100 mg plus gemcitabine were fatigue, rash and diarrhoea. In the erlotinib plus gemcitabine arm,

grade 3/4 rash and diarrhoea were each 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.

Table 1: ADRs occurring in ≥ 10% of patients in BR.21 (treated with erlotinib) and PA.3 (treated with

erlotinib plus gemcitabine) studies and ADRs occurring more frequently (≥ 3%) than placebo in BR.21

(treated with erlotinib) and PA.3 (treated with erlotinib plus gemcitabine) studies.

Erlotinib (BR.21)

N = 485

Erlotinib (PA.3)

N = 259

Frequency

category of

highest incidence

NCI-CTC Grade

Any

Grade

3

4

Any

Grade

3

4

MedDRA Preferred Term

%

%

%

%

%

%

Infections and infestations

Infection*

<1

very common

Metabolism and nutrition

disorders

Anorexia

very common

Weight decreased

very common

Eye disorders

Keratoconjunctivitis sicca

very common

Conjunctivitis

<1

very common

Psychiatric disorders

Depression

very common

Nervous system disorders

Neuropathy

<1

very common

Headache

<1

very common

Respiratory ,thoracic and

mediastinal disorders

Dyspnoea

very common

Cough

very common

Gastrointestinal disorders

Diarrhoea**

<1

<1

very common

Nausea

very common

Vomiting

<1

very common

Stomatitis

<1

<1

very common

Abdominal pain

<1

very common

Dyspepsia

<1

very common

Flatulence

very common

Skin and subcutaneous tissue

disorders

Rash***

<1

very common

Pruritus

<1

very common

Dry skin

very common

Alopecia

very common

General disorders and

administration site conditions

Fatigue

very common

Pyrexia

very common

Rigors

very common

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

** Can lead to dehydration, hypokalemia and renal failure.

*** Rash included dermatitis acneiform.

- corresponds to percentage below threshold.

Table 2: Summary of ADRs per frequency category.

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)

Very rare

(<1/10,000)

Eye disorders

Keratitis

Conjunctivitis

Eyelash

changes

Corneal

perforations

Corneal

ulcerations

Uveitis

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis

Interstitial lung

disease (ILD)

Gastrointestinal

disorders

Diarrhoea

Gastrointestinal

bleeding

Gastrointestinal

perforations

Hepato biliary

disorders

Liver function

test

abnormalities

Hepatic

failure

Skin and

subcutaneous

tissue disorders

Rash

Alopecia

Dry skin

Paronychia

Folliculitis

Acne/

Dermatitis

acneiform

Skin fissures

Hirsutism

Eyebrow

changes

Brittle and

loose nails

Mild skin

reactions such

as hyper-

pigmentation

Palmar

plantar

erythrodys-

aesthesia

syndrome

Stevens-

Johnson

syndrome/Toxic

epidermal

necrolysis

Renal and

urinary

disorders

Renal

insufficiency

Nephritis

Proteinuria

In clinical study PA.3.

Including in-growing eyelashes, excessive growth and thickening of the eyelashes.

Including fatalities, in patients receiving erlotinib for treatment of NSCLC or other advanced solid tumours (see

section 4.4). A higher incidence has been observed in patients in Japan (see section 4.4).

In clinical studies, some cases have been associated with concomitant warfarin administration and some with

concomitant NSAID administration (see section 4.5).

Including increased alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin. These were

very common in clinical study PA.3 and common in clinical study BR.21. Cases were mainly mild to moderate in

severity, transient in nature or associated with liver metastases.

Including fatalities. Confounding factors included pre-existing liver disease or concomitant hepatotoxic

medications (see section 4.4).

Including fatalities (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms

Single oral doses of erlotinib up to 1000 mg erlotinib in healthy subjects, and up to 1600 mg 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 reactions

such as diarrhoea, rash and possibly increased activity of liver aminotransferases may occur above the

recommended dose.

Management

In case of suspected overdose, erlotinib should be withheld and symptomatic treatment initiated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent, epidermal growth factor receptor (EGFR) tyrosine

kinase inhibitors, ATC code: L01EB02.

Mechanism of action

Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR

also known as HER1) tyrosine kinase inhibitor. Erlotinib potently inhibits the intracellular

phosphorylation of EGFR. EGFR is expressed on the cell surface of normal cells and cancer cells. In non-

clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.

EGFR mutations may lead to constitutive activation of anti-apoptotic and proliferation signalling

pathways. The potent effectiveness of erlotinib in blocking EGFR-mediated signalling in these EGFR

mutation positive tumours is attributed to the tight binding of erlotinib to the ATP-binding site in the

mutated kinase domain of the EGFR. Due to the blocking of downstream-signaling, the proliferation of

cells is stopped, and cell death is induced through the intrinsic apoptotic pathway. Tumour regression is

observed in mouse models of enforced expression of these EGFR activating mutations.

Clinical efficacy

First-line Non-Small Cell Lung Cancer (NSCLC) therapy for patients with EGFR activating mutations

(erlotinib administered as monotherapy):

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 daily or up to 4 cycles of platinum-

based doublet chemotherapy.

The primary endpoint was investigator assessed PFS. The efficacy results are summarised in Table 3.

Figure 1: Kaplan-Meier curve for investigator assessed PFS in trial ML20650 (EURTAC) (April 2012

cut-off).

Table 3: Efficacy results of erlotinib versus chemotherapy in trial ML20650 (EURTAC).

Erlotinib

Chemo-

therapy

Hazard

Ration

(95% CI)

p-value

n=77

n=76

Primary endpoint:

Progression Free Survival

(PFS, median in months)*

Investigator Assessed **

Independent Review **

10.4

0.42

[0.27-0.64]

0.47

[0.27-0.78]

p<0.0001

p=0.003

Best Overall Response

Rate (CR/PR)

54.5%

10.5%

p<0.0001

Pre-planned

Interim

Analysis (35%

OS maturity)

(n=153)

Cut-off date: Aug

2010

Overall Survival (OS)

(months)

22.9

18.8

0.80

[0.47-1.37]

p=0.4170

Exploratory

n=86

n=87

PFS (median in months),

Investigator assessed

0.37

[0.27-0.54]

p<0.0001

Best Overall Response

Rate

(CR/PR)

58.1%

14.9%

p<0.0001

Analysis

(40% OS

maturity)

(n=173)

Cut-off date: Jan

2011

OS (months)

19.3

19.5

1.04

[0.65-1.68]

p=0.8702

n=86

n=87

PFS (median in months)

10.4

0.34

[0.23-0.49]

p<0.0001

Updated

Analysis

(62% OS

maturity)

(n=173)

Cut-off date: April

2012

OS** (months)

22.9

20.8

0.93

[0.64-1.36]

p=0.7149

CR=complete response; PR=partial response

* A 58% reduction in the risk of disease progression or death was observed

** Overall concordance rate between investigator and IRC assessment was 70%

*** 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.

Maintenance NSCLC therapy after first-line chemotherapy (erlotinib administered as monotherapy):

The efficacy and safety of erlotinib as maintenance after first-line chemotherapy for 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 not progress after 4

cycles of platinum-based doublet chemotherapy. Patients were randomised 1:1 to receive erlotinib

150 mg or placebo orally once daily until disease progression. The primary endpoint of the study included

progression free survival (PFS) in all patients. Baseline demographic and disease characteristics were

well balanced between the two treatment arms. Patients with ECOG PS>1, significant hepatic or renal co-

morbidities were not included in the study.

In this study, 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). 67% of placebo patients in the EGFR mutation positive

subgroup received second or further line treatment with EGFR-TKIs.

The BO25460 (IUNO) study was conducted in 643 patients with advanced NSCLC whose tumors did not

harbor 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 tumor did not harbor 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.

NSCLC treatment after failure of at least one prior chemotherapy regimen (erlotinib administered as

monotherapy):

The efficacy and safety of erlotinib as second-/ third-line therapy was demonstrated in a randomised,

double-blind, placebo-controlled trial (BR.21), in 731 patients with locally advanced or metastatic

NSCLC after failure of at least one chemotherapy regimen. Patients were randomised 2:1 to receive

erlotinib 150 mg or placebo orally once daily. Study endpoints included overall survival, progression-free

survival (PFS), response rate, duration of response, time to deterioration of lung cancer-related symptoms

(cough, dyspnoea and pain), and safety. The primary endpoint was survival.

Demographic characteristics were well balanced between the two treatment groups. About 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.

The adjusted hazard ratio (HR) for death in the erlotinib group relative to the placebo group was 0.73

(95% CI, 0.60 to 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. The median overall survival was 6.7 months in the

erlotinib group (95% CI, 5.5 to 7.8 months) compared with 4.7 months in the placebo group (95% CI, 4.1

to 6.3 months).

The effect on overall survival was explored across different patient subsets. The effect of erlotinib on

overall survival was similar in patients with a baseline performance status (ECOG) of 2-3 (HR = 0.77,

95% CI 0.6-1.0) or 0-1 (HR = 0.73, 95% CI 0.6-0.9), male (HR = 0.76, 95% CI 0.6-0.9) or female

patients (HR = 0.80, 95% CI 0.6-1.1), patients < 65 years of age (HR = 0.75, 95% CI 0.6-0.9) or older

patients (HR = 0.79, 95% CI 0.6-1.0), patients with one prior regimen (HR = 0.76, 95% CI 0.6-1.0) or

more than one prior regimen (HR = 0.75, 95% CI 0.6-1.0), Caucasian (HR = 0.79, 95% CI 0.6-1.0) or

Asian patients (HR = 0.61, 95% CI 0.4-1.0), patients with adenocarcinoma (HR = 0.71, 95% CI 0.6-0.9)

or squamous cell carcinoma (HR = 0.67, 95% CI 0.5-0.9), but not in patients with other histologies (HR

1.04, 95% CI 0.7-1.5), patients with stage IV disease at diagnosis (HR = 0.92, 95% CI 0.7-1.2) or < stage

IV disease at diagnosis (HR = 0.65, 95% CI 0.5-0.8). Patients who never smoked had a much greater

benefit from erlotinib (survival HR = 0.42, 95% CI 0.28-0.64) compared with current or ex-smokers

(HR = 0.87, 95% CI 0.71-1.05).

In the 45% of patients with known EGFR-expression status, the hazard ratio was 0.68 (95% CI 0.49-0.94)

for patients with EGFR-positive tumours and 0.93 (95% CI 0.63-1.36) for patients with EGFR-negative

tumours (defined by IHC using EGFR pharmDx kit and defining EGFR-negative as less than 10% tumour

cells staining). In the remaining 55% of patients with unknown EGFR-expression status, the hazard ratio

was 0.77 (95% CI 0.61-0.98).

The median PFS was 9.7 weeks in the erlotinib group (95% CI, 8.4 to 12.4 weeks) compared with 8.0

weeks in the placebo group (95% CI, 7.9 to 8.1 weeks).

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

330 patients were centrally assessed (response rate 6.2%); 401 patients were investigator assessed

(response rate 11.2%).

The median duration of response was 34.3 weeks, ranging from 9.7 to 57.6+ weeks. 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).

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 hazard ratio for death of 0.82 (95% CI, 0.68 to 0.99)

among patients whose best response was stable disease or progressive disease.

Erlotinib resulted in symptom benefits by significantly prolonging time to deterioration in cough,

dyspnoea and pain, versus placebo.

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

(300 mg versus 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).

Secondary efficacy endpoints were all consistent with the primary endpoint and no difference was

detected for OS between patients treated with erlotinib 300 mg and 150 mg daily (HR 1.03, 95% CI 0.80

to 1.32). Safety data were comparable between the 300 mg and 150 mg doses; however, there was a

numerical increase in the incidence of rash, interstitial lung disease and diarrhoea, in patients receiving

the higher dose of erlotinib. Based on the data from the CURRENTS study, no evidence was seen for any

benefit of a higher erlotinib dose of 300 mg when compared with the recommended dose of 150 mg in

active smokers.

Patients in this study were not selected based on EGFR mutation status. See sections 4.2, 4.4, 4.5, and 5.2.

Pancreatic cancer (erlotinib administered concurrently with gemcitabine in study PA.3):

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 patients with locally advanced, unresectable or

metastatic pancreatic cancer. Patients were randomised to receive erlotinib or placebo once daily on a

continuous schedule plus gemcitabine IV (1000 mg/m2, 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, see the gemcitabine SPC]). Erlotinib or placebo was taken orally once

daily until disease progression or unacceptable toxicity. The primary endpoint was overall survival.

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

groups, 100 mg erlotinib plus gemcitabine or placebo plus gemcitabine, except for a slightly larger

proportion of females in the erlotinib/gemcitabine arm compared with the placebo/gemcitabine arm:

Baseline

Erlotinib

Placebo

Females

Baseline ECOG performance status (PS) = 0

Baseline ECOG performance status (PS) = 1

Baseline ECOG performance status (PS) = 2

Metastatic disease at baseline

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

shown in the table below (results for the group of metastatic and locally advanced patients are derived

from exploratory subgroup analysis).

Outcome

Erlotinib

(months)

Placebo

(months)

Δ

(months)

CI of Δ

HR

CI of

HR

P-

value

Overall Population

Median overall survival

0.41

-0.54-1.64

Mean overall survival

1.16

-0.05-2.34

0.82

0.69-0.98

0.028

Metastatic Population

Median overall survival

0.87

-0.26-1.56

Mean overall survival

1.43

0.17-2.66

0.80

0.66-0.98

0.029

Locally Advanced Population

Median overall survival

0.36

-2.43-2.96

Mean overall survival

10.7

10.5

0.19

-2.43-2.69

0.93

0.65-1.35

0.713

In a post-hoc analysis, patients with favourable clinical status at baseline (low pain intensity, good QoL

and good PS) may derive more benefit from erlotinib. The benefit is mostly driven by the presence of a

low pain intensity score.

In a post-hoc analysis, patients on erlotinib who developed a rash had a longer overall survival compared

to patients who did not develop rash (median OS 7.2 months vs 5 months, HR:0.61). 90% of patients on

erlotinib developed rash within the first 44 days. The median time to onset of rash was 10 days.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with erlotinib

in all subsets of the paediatric population in Non Small Cell Lung Cancer and Pancreatic cancer

indications (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

After oral administration, erlotinib peak plasma levels are obtained in approximately 4 hours after oral

dosing. A study in normal healthy volunteers provided an estimate of the absolute bioavailability of 59%.

The exposure after an oral dose may be increased by food.

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 1185 ng/g of tissue. This

corresponded to an overall average of 63% (range 5-161%) of the steady state observed peak plasma

concentrations. The primary active metabolites were present in tumour at concentrations averaging

160 ng/g tissue, which corresponded to an overall average of 113% (range 88-130%) of the observed

steady state peak plasma concentrations. Plasma protein binding is approximately 95%. Erlotinib binds to

serum albumin and alpha-1 acid glycoprotein (AAG).

Biotransformation

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a

lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and 1B1

in tumour tissue potentially contribute to the metabolic clearance of erlotinib.

There are three 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 OSI-420 and OSI-413 of erlotinib produced by O-demethylation of either side chain

have comparable potency to erlotinib in non-clinical

in vitro

assays and

in vivo

tumour models. They are

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

Elimination

Erlotinib is excreted predominantly as metabolites via the faeces (>90%) with renal elimination

accounting for only a small amount (approximately 9%) of an oral dose. Less than 2% of the orally

administered dose is excreted as parent substance. A population pharmacokinetic analysis in 591 patients

receiving single agent erlotinib shows 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.

Pharmacokinetics in special populations

Based on population pharmacokinetic analysis, no clinically significant relationship between predicted

apparent clearance and patient age, bodyweight, gender and ethnicity were observed. Patient factors,

which correlated with erlotinib pharmacokinetics, were serum total bilirubin, AAG and current smoking.

Increased serum concentrations of total bilirubin and AAG concentrations were associated with a reduced

erlotinib clearance. The clinical relevance of these differences is unclear. However, smokers had an

increased rate of erlotinib clearance. This was confirmed in a pharmacokinetic study in non-smoking and

currently cigarette smoking healthy subjects receiving a single oral dose of 150 mg erlotinib. The

geometric mean of the C

was 1056 ng/ml in the non-smokers and 689 ng/ml in the smokers with a

mean ratio for smokers to non-smokers of 65.2% (95% CI: 44.3 to 95.9, p = 0.031). The geometric mean

of the AUC

0-inf

was 18726 ngh/ml in the non-smokers and 6718 ngh/ml in the smokers with a mean ratio

of 35.9% (95% CI: 23.7 to 54.3, p < 0.0001). The geometric mean of the C

was 288 ng/ml in the non-

smokers and 34.8 ng/ml in the smokers with a mean ratio of 12.1% (95% CI: 4.82 to 30.2, p = 0.0001).

In the pivotal Phase III NSCLC trial, current smokers achieved 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. In a phase I dose escalation study in NSCLC patients who were

current smokers, 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. Steady-state trough plasma concentrations at a 300 mg dose in current smokers in this study was

1.22 μg/ml (n=17). See sections 4.2, 4.4, 4.5 and 5.1.

Based on the results of pharmacokinetic studies, current smokers should be advised to stop smoking while

taking erlotinib, as plasma concentrations could be reduced otherwise.

Based on population pharmacokinetic analysis, the presence of an opioid appeared to increase exposure

by about 11%.

A second population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204

pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis demonstrated that

covariants affecting erlotinib clearance in patients from the pancreatic study 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.

Paediatric population: There have been no specific studies in paediatric patients.

Elderly population: There have been no specific studies in elderly patients.

Hepatic impairment: Erlotinib is primarily cleared by the liver. In patients with solid tumours and with

moderately impaired hepatic function (Child-Pugh score 7-9), geometric mean erlotinib AUC

and C

was 27000 ngh/ml and 805 ng/ml, respectively, as compared to 29300 ngh/ml and 1090 ng/ml in

patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.

Although the C

was statistically significant lower in moderately hepatic impaired patients, this

difference is not considered clinically relevant. No data are available regarding the influence of severe

hepatic dysfunction on the pharmacokinetics of erlotinib. In population pharmacokinetic analysis,

increased serum concentrations of total bilirubin were associated with a slower rate of erlotinib clearance.

Renal impairment: Erlotinib and its metabolites are not significantly excreted by the kidney, as less than

9% of a single dose is excreted in the urine. In population pharmacokinetic analysis, no clinically

significant relationship was observed between erlotinib clearance and creatinine clearance, but there are

no data available for patients with creatinine clearance <15 ml/min.

5.3 Preclinical safety data

Chronic dosing effects observed in at least one animal species or study included effects on the cornea

(atrophy, ulceration), skin (follicular degeneration and inflammation, redness, and alopecia), ovary

(atrophy), liver (liver necrosis), kidney (renal papillary necrosis and tubular dilatation), and

gastrointestinal tract (delayed gastric emptying and diarrhoea). Red blood cell parameters were decreased

and white blood cells, primarily neutrophils, were increased. There were treatment-related increases in

ALT, AST and bilirubin. These findings were observed at exposures well below clinically relevant

exposures.

Based on the mode of action, erlotinib has the potential to be a teratogen. Data from reproductive

toxicology tests in rats and rabbits at doses near the maximum tolerated dose and/or maternally toxic

doses showed reproductive (embryotoxicity in rats, embryo resorption and foetotoxicity in rabbits) and

developmental (decrease in pup growth and survival in rats) toxicity, but was not teratogenic and did not

impair fertility. These findings were observed at clinically relevant exposures.

Erlotinib tested negative in conventional genotoxicity studies. Two-year carcinogenicity studies with

erlotinib conducted in rats and mice were negative up to exposures exceeding human therapeutic

exposure (up to 2-fold and 10-fold higher, respectively, based on C

and/or AUC).

A mild phototoxic skin reaction was observed in rats after UV irradiation.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose

Cellulose, microcrystalline

Croscarmellose sodium

Magnesium stearate

Silica, colloidal anhydrous

Tablet coat:

Hypromellose

Hydroxypropylcellulose

Triethyl citrate

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Clear PVC/Aclar blister with aluminum foil containing 30 tablets.

6.6 Special precautions for disposal

No special requirements for disposal.

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

requirements.

7. MARKETING AUTHORISATION HOLDER

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

2021-03-15

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