Consumer medicine information

Giotrif

Afatinib

BRAND INFORMATION

Brand name

Giotrif

Active ingredient

Afatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Giotrif.

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.medicines.org.au 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.

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:

  1. Drop the tablet into half a glass of drinking water (non-carbonated) (Do not break or crush the tablet)
  2. Stir the water occasionally for up to 15 minutes until the tablet is broken up into very small particles
  3. Drink the liquid straight away
  4. Rinse the empty glass with half a glass of drinking water and drink it.

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. 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 (Australia telephone 13 11 26; New Zealand 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, 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 eye
  • 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 distributed in Australia.

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:

  • lactose monohydrate
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • 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 Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney, Australia
www.boehringer-ingelheim.com.au

Giotrif is supplied in New Zealand by:

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 June 2019.

Australian Registration Numbers

GIOTRIF 20 mg AUST R 201314

GIOTRIF 30 mg AUST R 201318

GIOTRIF 40 mg AUST R 201315

GIOTRIF 50 mg AUST R 201320

Published by MIMS August 2019

BRAND INFORMATION

Brand name

Giotrif

Active ingredient

Afatinib

Schedule

S4

 

1 Name of Medicine

Afatinib (as afatinib dimaleate).

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: One film-coated tablet contains 118 mg lactose (as monohydrate).

Giotrif 30 mg film-coated tablets.

One film-coated tablet contains 30 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 176 mg lactose (as monohydrate).

Giotrif 40 mg film-coated tablets.

One film-coated tablet contains 40 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 235 mg lactose (as monohydrate).

Giotrif 50 mg film-coated tablets.

One film-coated tablet contains 50 mg afatinib (as dimaleate).
Excipient with known effect: One film-coated tablet contains 294 mg lactose (as monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Giotrif 20 mg tablets are film-coated white to slightly yellowish, round, biconvex and bevel-edged. One side is debossed with the code "T20", the other side is debossed with the Boehringer Ingelheim company symbol.
Giotrif 30 mg tablets are film-coated dark blue, round, biconvex and bevel-edged. One side is debossed with the code "T30", the other side is debossed with the Boehringer Ingelheim company symbol.
Giotrif 40 mg tablets are film-coated light blue, round, biconvex and bevel-edged. One side is debossed with the code "T40", the other side is debossed with the Boehringer Ingelheim company symbol.
Giotrif 50 mg tablets are film-coated dark blue, oval and biconvex. One side is debossed with the code "T50", the other side is debossed with the Boehringer Ingelheim company symbol.

4 Clinical Particulars

4.1 Therapeutic Indications

Giotrif is indicated as monotherapy for the treatment of adult 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 activating epidermal growth factor receptor (EGFR) mutations.
Locally advanced or metastatic squamous non-small cell carcinoma of the lung progressing on or after platinum-based chemotherapy.

4.2 Dose and Method of Administration

The recommended dose of Giotrif is 40 mg orally once daily.
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 Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use). Tablets should be swallowed whole with water.
Giotrif treatment should be continued until disease progression or until no longer tolerated by the patient (see Table 1).

Dosage adjustment.

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 managed by treatment interruption and dose reductions of Giotrif as outlined in Table 1 (see Section 4.8 Adverse Effects (Undesirable Effects); for further details on management of specific drug related adverse events, see Section 4.4 Special Warnings and Precautions for Use).
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 Special Warnings and Precautions for Use).

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.

Patients with severe renal impairment have a higher exposure to afatinib than patients with normal renal function. Administer Giotrif at a starting dose of 30 mg once daily in patients with severe renal impairment. Adjustments to the starting dose of Giotrif are not necessary in patients with mild or moderate renal impairment. Dosing recommendations for patients with eGFR < 15 mL/min/1.73 m2 or on dialysis cannot be provided as Giotrif has not been studied in these patient populations.

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 Pharmacokinetic Properties). 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 Pharmacokinetic Properties).

Paediatric population.

The safety and efficacy of Giotrif have not been established in paediatric patients.
Treatment of children or adolescents with Giotrif was not supported by a clinical trial conducted in paediatric patients and is therefore 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 Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Alternative method of administration.

If dosing of whole tablets is not possible, Giotrif tablets can be dispersed in approximately 100 mL of noncarbonated 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.

4.3 Contraindications

Giotrif is contraindicated in patients with known hypersensitivity to afatinib or to any of the excipients.

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 Adverse Effects (Undesirable Effects)). 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 of 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 Dose and Method of Administration). 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 Adverse Effects (Undesirable Effects)). 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 sunscreen 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 Dose and Method of Administration), 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 bodyweight and underlying renal impairment.

Higher exposure to afatinib has been observed in female patients, patients with lower bodyweight and those with underlying renal impairment (see Section 5.2 Pharmacokinetic Properties). 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 Adverse Effects (Undesirable Effects)). Patients with a history of ILD have not been studied. Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Giotrif should be interrupted pending investigation of these symptoms. If ILD is diagnosed, Giotrif should be permanently discontinued and appropriate treatment instituted as necessary (see Section 4.2 Dose and Method of Administration).

Use in 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 comorbidities 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 Dose and Method of Administration). In patients who develop severe hepatic impairment while taking Giotrif, treatment should 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 use is also a risk factor for keratitis and ulceration (see Section 4.8 Adverse Effects (Undesirable Effects)).

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 as well as Giotrif treatment interruption or discontinuation should be considered.

Pancreatitis.

Adverse events of pancreatitis have been observed uncommonly in patients treated with Giotrif. Although a causal association was not established, patients who 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 Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Lactose monohydrate.

Giotrif contains lactose monohydrate. Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Phototoxicity.

An in vitro mouse 3T3 cell phototoxicity test with afatinib was performed. It was concluded that Giotrif may have phototoxicity potential. See Section 4.4 Special Warnings and Precautions for Use, Skin related adverse events.

Food effect on afatinib.

Coadministration 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 AUC0-∞. Giotrif should be administered without food (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 to ritonavir, ciclosporin A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) may increase exposure to afatinib and should be used with caution (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Strong P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital or St. John's wort) may decrease exposure to afatinib (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

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 coadministrating Giotrif and BCRP substrates.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies in humans have not been performed with Giotrif. Available nonclinical toxicology data have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of Giotrif therapy on human fertility cannot be excluded.
A fertility study in male and female rats by the oral route up to the maximum tolerated dose revealed no significant impact on fertility. Postimplantation loss was increased at the highest dose. The systemic exposure (AUC0-24) achieved in male and female rats was similar to or less than that observed in patients (1.3 times and 0.51 times, respectively).
(Category C)
Based on the mechanism of action, Giotrif has the potential to cause fetal harm. The embryofetal development studies in rats and rabbits on afatinib revealed no indication of teratogenicity up to dose levels (16 mg/kg/day in rats and 10 mg/kg/day in rabbits) including maternal death. However, afatinib showed very limited placental transfer in rats. Changes identified were reduced fetal weights (rat and rabbit), abortions (rabbit), and skeletal alterations (flexure of extremities, abnormal rib curvature, lumbar ribs) and dermal variation (less integument of forelimbs) (rabbit). The systemic exposures (AUC), achieved in these experiments were either slightly above (2.2 times in rats) or below (0.3 times in rabbits) the exposure in patients.
There are no studies in pregnant women using Giotrif. It is unknown whether afatinib crosses the placenta in humans. Therefore, the potential risk for humans is thus unknown. 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. 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 fetus.
 Radiolabelled afatinib administered orally to lactating rats was excreted into milk. The average concentrations in milk at time points 1 h and 6 h postdose were approximately 80 and 150-fold above the respective concentration in plasma.
Based on nonclinical data it is likely that afatinib is excreted in human milk. A risk to the nursing child cannot be excluded. Mothers should be advised against breastfeeding while receiving Giotrif.
A study in rats by the oral route up to the maximum tolerated dose revealed no significant impact on the attainment of developmental landmarks, sexual maturation or performance by behavioural assessments. Effects were limited to lower birthweight and bodyweight gain of offspring. The highest total systemic exposure (AUC0-24) achieved in female rats was less than that observed in patients (0.23 times).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive or operate machinery have been performed.

4.8 Adverse Effects (Undesirable Effects)

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 was higher in the Giotrif treated patients than in those patients treated with pemetrexed/ cisplatin, respectively.
Dose reductions due to adverse events (AEs) 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 (Table 2).
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 (Table 2).
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 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.
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 3.
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 Special Warnings and Precautions for Use).

All NSCLC-studies with daily doses 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 (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use), 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 4.
One patient (0.2%) receiving a 40 mg starting dose experienced grade 4 rash/ acne.
A summary of common ADRs of diarrhoea and rash/acne in patients with squamous NSCLC treated with Giotrif monotherapy in the LUX-Lung 8 trial is provided in Table 5.
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 diarrhoea and rash/acne regardless of severity grade occurred in 3.8% and 2.0% of patients.
The ADRs pooled from all NSCLC trials with daily starting doses of 40 and 50 mg Giotrif as monotherapy and postmarketing experience are shown by system organ class (see Table 6). 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).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other antineoplastic agents - protein kinase inhibitors, ATC code: L01EB03.

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 non-clinical 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. NSCLC models with either exon 21 L858R substitution (L858R) or exon 19 deletion (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 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 trials.

Non-small cell lung cancer (NSCLC).

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 either Giotrif 40 mg orally once daily (N = 230) or up to 6 cycles of 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 tolerated.
Among the patients randomised, 65% were female, the median age was 61 years, 12% had brain metastases, ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The majority of patients had a tumour sample with an EGFR mutation categorised as either Del 19 (49%) or L858R (40%), and the remaining 11% had other mutations.
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 predefined subgroup 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. The Kaplan-Meier curves for the primary PFS analysis in common mutations are shown in Figure 1.
Subgroup analyses were conducted based on the stratification factor of EGFR mutation status (Del19, L858R, other) and mutation category (common [Del19, L858R] vs. uncommon [other]). See Figure 2.
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), deletion 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 7.
The effect on PFS was consistent across major subgroups, including gender, age, race, ECOG status, and mutation type (L858R, Del 19). The median OS with first-line Giotrif vs. chemotherapy was not significantly different in the common EGFR mutations (Del19 and L858R) subgroup (31.6 months vs. 28.2 months, HR = 0.78, 95% CI [0.58, 1.06], p = 0.1090) or the L858R subgroup (27.6 months vs. 40.3 months, HR = 1.30, 95% CI [0.80, 2.11], p = 0.2919), but was significantly different for the Del19 subgroup (33.3 months vs. 21.1 months, HR = 0.54, 95% CI [0.36, 0.79], p = 0.0015).
Disease-related symptoms were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). Statistically significant increases in time-to-worsening of pre-specified symptoms 'cough' and 'dyspnoea', and improvements in dyspnoea and pain were seen in the afatinib arm, compared to the chemotherapy arm. However, these results may have been affected by the open-label nature of the trial.

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 randomized 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 pre-specified 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 46.9% vs. 2.3% in the subgroup of common mutations.
The Kaplan-Meier curves of the primary PFS analysis are shown in Figure 3, and efficacy results are summarised in Table 8. At the time of primary PFS analysis, 48 (19.8%) patients treated with Giotrif and 8 (6.6%) patients treated with chemotherapy were known to be alive and progression-free.
Disease-related symptoms were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). Statistically significant increases in time-to-worsening of pre-specified symptoms 'cough', 'dyspnoea' and 'pain', and improvements in cough, dyspnoea and pain were seen in the afatinib arm, compared to the chemotherapy arm. However, these results may have been affected by the open-label nature of the trial.

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).
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 9) 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.
The PFS hazard ratio for patients with Del 19 mutations and L858R mutations was 0.76 (95% CI [0.55, 0.65]; 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-naïve 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 LUX-Lung 2, EGFR status was determined by bi-directional Sanger sequencing of tumour tissue; in LUX-Lung 3 and LUX-Lung 6, EGFR status was determined by the TheraScreen EGFR RGQ PCR Kit.
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 (Table 10).
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.
The efficacy and safety of Giotrif as second line treatment of patients with NSCLC of squamous histology was investigated in an open-label active controlled trial LUX-Lung 8.
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.
Baseline patient demographics of the 795 patients were: median age 64 years (range: 35 to 88); 73% white; 24% Asian; 84% male; 33% ECOG performance status (PS) 0 and 67% ECOG PS 1; and 92% current or former smokers.
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 month 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 11). 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 on erlotinib. The mean duration of treatment was 120.8 days in the Giotrif group and 97.2 days in the erlotinib group; the maximum duration of treatment was 840 days in the Giotrif group and 619 days in the erlotinib group. See Table 11 and Figure 4.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of Giotrif, maximum concentrations (Cmax) of afatinib are observed approximately 2 to 5 hours postdose. Mean Cmax and AUC0-∞ 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% (Cmax) and 39% (AUC0-∞), 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 AUCT,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 and at least 1 hour after taking Giotrif (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). After administration of Giotrif, the mean relative bioavailability was 92% (adjusted gMean ratio of AUC0-∞) 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%.

Metabolism.

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.

Excretion.

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 (Cmax).

Renal impairment.

Less than 5% of a single dose of afatinib is excreted via the kidneys. Exposure to afatinib in otherwise healthy volunteers with renal impairment (based on estimated glomerular filtration rate [eGFR] according to MDRD formula) following a single dose of 40 mg Giotrif was compared with that in matched controls. Subjects with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2; N = 8) and subjects with severe renal impairment (eGFR 15-29 mL/min/1.73 m2; N = 8) had geometric mean exposures (AUC) approximately 20% and 50% higher, respectively, than matched controls (N = 8). Giotrif has not been studied in patients with eGFR < 15 mL/min/1.73 m2 or 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 Pharmacokinetic analysis in target populations). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment (see Section 4.2 Dose and Method of Administration). The pharmacokinetics of afatinib had not been studied in subjects with severe (Child-Pugh C) hepatic dysfunction (see Section 4.4 Special Warnings and Precautions for Use).

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.

Bodyweight.

Plasma exposure (AUCT,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 bodyweight of patients in the overall patient population).

Gender.

Female patients had a 15% higher plasma exposure (AUCT,ss, bodyweight corrected) than 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 (AUCT,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. The relative bioavailability of afatinib was 119% (AUC0-∞) and 104% (Cmax) when administered simultaneously with ritonavir and 111% (AUC0-∞) and 105% (Cmax) when ritonavir was administered 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% (AUC0-∞) and 39% (Cmax) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.2 Dose and Method of Administration).
Pretreatment with rifampicin (600 mg q.d. for 7 days), a potent inducer of P-gp, decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) after administration of a single dose of 40 mg Giotrif (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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. In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATP1B1, 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

Genotoxicity.

Afatinib was weakly positive in one bacterial strain in a (Ames) mutagenicity assay and induced chromosome aberrations in human lymphocytes in vitro at a cytotoxic concentration. However, testing in the Muta Mouse in vivo mutagenicity assay at oral doses up to 47 mg/kg for 4 weeks, in the rat bone marrow micronucleus assays at up to 32 mg/kg/day for 2 weeks and 18 mg/kg/day for 4 weeks (7 and 4 times, respectively, the clinical exposure based on AUC), and in the Comet assay (detecting DNA damage) using cells from rats given two doses at 200 mg/kg, showed no evidence of genotoxicity.
The balance of evidence indicates that afatinib is unlikely to pose a genotoxic risk to patients.

Carcinogenicity.

Carcinogenicity studies have not been conducted with afatinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica, crospovidone, magnesium stearate.
Film coating: 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).

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 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

Giotrif 20 mg are supplied in packs of 7*, 14* and 28 tablets.
Giotrif 30 mg are supplied in packs of 7*, 14* and 28 tablets.
Giotrif 40 mg are supplied in packs of 7*, 14* and 28 tablets.
Giotrif 50 mg are supplied in packs of 7*, 14* and 28 tablets.
Seven Giotrif film-coated tablets are packed in one perforated unit dose blister card consisting of a PVC/PVDC forming sheet and an aluminium lidding foil. One blister card is packed together with a desiccant sachet in a laminated aluminium pouch. One, two or four pouches are packed into a carton box resulting in pack sizes of 7*, 14* or 28 film-coated tablets per pack, respectively.
* Not distributed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

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 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).

Chemical structure.

Chemical name: 2-butenamide, N-[4-[3(-chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate (1:2).
Molecular formula: C24H25ClFN5O3 x 2C4H4O4 or C32H33ClFN5O11.
Molecular weight: 718.1 g/mol (salt form); 485.9 g/mol (free base).
Structural formula:

CAS number.

850140-73-7 (salt form); 850140-72-6 (free base).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes