GIOTRIF 40mg tablets medication leaflet

GIOTRIF 20 mg film-coated tablets

GIOTRIF 30 mg film-coated tablets

GIOTRIF 40 mg film-coated tablets

GIOTRIF 50 mg film-coated tablets

GIOTRIF 20 mg film-coated tablets

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

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).

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).

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).

One film-coated tablet contains 294 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

GIOTRIF 20 mg film-coated tablets

White to yellowish, round, biconvex and bevel-edged film-coated tablet debossed with the code “T20”on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF 30 mg film-coated tablets

Dark blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T30” on oneside and the Boehringer Ingelheim company logo on the other.

GIOTRIF 40 mg film-coated tablets

Light blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T40” on oneside and the Boehringer Ingelheim company logo on the other.

GIOTRIF 50 mg film-coated tablets

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

Boehringer Ingelheim company logo on the other.

GIOTRIF as monotherapy is indicated for the treatment of

* Epidermal Growth Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced ormetastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s);

* Adult patients with locally advanced or metastatic NSCLC of squamous histology progressingon or after platinum-based chemotherapy (see section 5.1).

Treatment with GIOTRIF should be initiated and supervised by a physician experienced in the use ofanticancer therapies.

EGFR mutation status should be established prior to initiation of GIOTRIF therapy (see section 4.4).

The recommended dose is 40 mg once daily.

This medicinal product should be taken without food. Food should not be consumed for at least3 hours before and at least 1 hour after taking this medicinal product (see sections 4.5 and 5.2).

GIOTRIF treatment should be continued until disease progression or until no longer tolerated by thepatient (see Table 1 below).

A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/daystarting dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE

Grade > 1) in the first cycle of treatment (21 days for EGFR mutation positive NSCLC and 28 days forsquamous NSCLC). The dose should not be escalated in any patients with a prior dose reduction. Themaximum daily dose is 50 mg.

Dose adjustment for adverse reactions

Symptomatic adverse reactions (e.g. severe/persistent diarrhoea or skin related adverse reactions) maybe successfully managed by treatment interruption and dose reductions or treatment discontinuation of

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

Table 1: Dose adjustment information for adverse reactions

CTCAEa Adverse reactions Recommended dosing

Grade 1 or Grade 2 No interruption b No dose adjustment

Grade 2 (prolonged c or intolerable) or Interrupt until Resume with dose

Grade > 3 Grade 0/1 b reduction by 10 mgdecrements da NCI Common Terminology Criteria for Adverse Eventsb In case of diarrhoea, anti-diarrhoeal medicinal products (e.g. loperamide) should be taken immediately andcontinued for persistent diarrhoea until loose bowel movements cease.c > 48 hours of diarrhoea and/or > 7 days of rashd If patient cannot tolerate 20 mg/day, permanent discontinuation of GIOTRIF should be considered

Interstitial Lung Disease (ILD) should be considered if a patient develops acute or worsening ofrespiratory symptoms in which case treatment should be interrupted pending evaluation. If ILD isdiagnosed, GIOTRIF should be discontinued and appropriate treatment initiated as necessary(see section 4.4).

If a dose is missed, it should be taken within 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.

Use of P-glycoprotein (P-gp) inhibitors

If P-gp inhibitors need to be taken, they should be administered using staggered dosing, i.e. the P-gpinhibitor dose should be taken as far apart in time as possible from the GIOTRIF dose. This meanspreferably 6 hours (for P-gp inhibitors dosed twice daily) or 12 hours (for P-gp inhibitors dosed oncedaily) apart from GIOTRIF (see section 4.5).

Exposure to afatinib was found to be increased in patients with moderate or severe renal impairment(see section 5.2). Adjustments to the starting dose are not necessary in patients with mild(eGFR 60-89 mL/min/1.73 m²), moderate (eGFR 30-59 mL/min/1.73 m²) or severe(eGFR 15-29 mL/min/1.73 m²) renal impairment. Monitor patients with severe renal impairment(eGFR 15-29 mL/min/1.73 m²) and adjust GIOTRIF dose if not tolerated.

GIOTRIF treatment in patients with eGFR < 15 mL/min/1.73 m² or on dialysis is not recommended.

Exposure to afatinib is not significantly changed in patients with mild (Child Pugh A) or moderate(Child Pugh B) hepatic impairment (see section 5.2). Adjustments to the starting dose are notnecessary in patients with mild or moderate hepatic impairment. This medicinal product has not beenstudied in patients with severe (Child Pugh C) hepatic impairment. Treatment in this population is notrecommended (see section 4.4).

There is no relevant use of GIOTRIF in the paediatric population in the indication of NSCLC.

Treatment of children or adolescents with GIOTRIF was not supported by a clinical trial conducted inpaediatric patients with other conditions (see sections 5.1 and 5.2). Safety and efficacy have not beenestablished.

Therefore, treatment of children or adolescents with this medicinal product is not recommended.

This medicinal product is for oral use. The tablets should be swallowed whole with water. Ifswallowing of whole tablets is not possible, these can be dispersed in approximately 100 mL ofnon-carbonated drinking water. No other liquids should be used. The tablet should be dropped into thewater without crushing it, and stirred occasionally for up to 15 min until it is broken up into very smallparticles. The dispersion should be consumed immediately. The glass should be rinsed withapproximately 100 mL of water which should also be consumed. The dispersion can also beadministered through a gastric tube.

Hypersensitivity to afatinib or to any of the excipients listed in section 6.1.

Assessment of EGFR mutation status

When assessing the EGFR mutation status of a patient, it is important that a well-validated and robustmethodology is chosen to avoid false negative or false positive determinations.

Diarrhoea, including severe diarrhoea, has been reported during treatment with GIOTRIF(see section 4.8). Diarrhoea may result in dehydration with or without renal impairment, which in rarecases has resulted in fatal outcomes. 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 anti-diarrhoealmedicinal products especially within the first 6 weeks of the treatment is important and should start atfirst signs of diarrhoea. Antidiarrhoeal medicinal products (e.g. loperamide) should be used and ifnecessary their dose should be escalated to the highest recommended approved dose. Anti-diarrhoealmedicinal products should be readily available to the patients so that treatment can be initiated at firstsigns of diarrhoea and continued until loose bowel movements cease for 12 hours. Patients with severediarrhoea may require interruption and dose reduction or discontinuation of therapy with GIOTRIF(see section 4.2). Patients who become dehydrated may require administration of intravenouselectrolytes and fluids.

Skin related adverse events

Rash/acne has been reported in patients treated with this medicinal product (see section 4.8). Ingeneral, rash manifests as a mild or moderate erythematous and acneiform rash, which may occur orworsen in areas exposed to sun. For patients who are exposed to sun, protective clothing, and use ofsun screen is advisable. Early intervention (such as emollients, antibiotics) of dermatologic reactionscan facilitate continuous GIOTRIF treatment. Patients with severe skin reactions may also requiretemporary interruption of therapy, dose reduction (see section 4.2), additional therapeutic intervention,and referral to a specialist with expertise in managing these dermatologic effects.

Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestiveof Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment with this medicinal productshould be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliatingconditions (see section 4.8).

Female gender, lower body weight, and underlying renal impairment

Higher exposure to afatinib has been observed in female patients, patients with lower body weight andthose with underlying renal impairment (see section 5.2). This could result in a higher risk ofdeveloping adverse reactions in particular diarrhoea, rash/acne and stomatitis. Closer monitoring isrecommended in patients with these risk factors.

Interstitial Lung Disease (ILD)

There have been reports of ILD or ILD-like adverse reactions (such as lung infiltration, pneumonitis,acute respiratory distress syndrome, allergic alveolitis), including fatalities, in patients receiving

GIOTRIF for treatment of NSCLC. ILD-like adverse reactions were reported in 0.7% of patientstreated with GIOTRIF across all clinical trials (including 0.5% of patients with CTCAE Grade ≥ 3

ILD-like adverse reactions). Patients with a history of ILD have not been studied.

Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonarysymptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with thismedicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed,

GIOTRIF should be permanently discontinued and appropriate treatment initiated as necessary(see section 4.2).

Hepatic failure, including fatalities, has been reported during treatment with this medicinal product inless than 1% of patients. In these patients, confounding factors have included pre-existing liver diseaseand/or comorbidities associated with progression of underlying malignancy. Periodic liver functiontesting is recommended in patients with pre-existing liver disease. In the pivotal trials Grade 3 alanineaminotransferase (ALT) and aspartate aminotransferase (AST) elevations were observed in 2.4%(LUX-Lung-3) and 1.6% (LUX-Lung 8) of patients with normal baseline liver tests treated with40 mg/day. In LUX-Lung-3 Grade 3 ALT/AST elevations were about 3.5 fold higher in patients withabnormal baseline liver tests. There were no Grade 3 ALT/AST elevations in patients with abnormalbaseline liver tests in LUX-Lung 8 (see section 4.8). Dose interruption may become necessary inpatients who experience worsening of liver function (see section 4.2). In patients who develop severehepatic impairment while taking GIOTRIF, treatment should be discontinued.

Gastrointestinal perforation, including fatalities, has been reported during treatment with GIOTRIF in0.2% of patients across all randomized controlled clinical trials. In the majority of cases,gastrointestinal perforation was associated with other known risk factors, including concomitantmedications such as corticosteroids, NSAIDs, or anti-angiogenic agents, an underlying history ofgastrointestinal ulceration, underlying diverticular disease, age, or bowel metastases at sites ofperforation. In patients who develop gastrointestinal perforation while taking GIOTRIF, treatmentshould 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 ofulcerative keratitis is confirmed, treatment should be interrupted or discontinued. If keratitis isdiagnosed, the benefits and risks of continuing treatment should be carefully considered. Thismedicinal product should be used with caution in patients with a history of keratitis, ulcerativekeratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration(see section 4.8).

Left ventricular function

Left ventricular dysfunction has been associated with HER2 inhibition. Based on the available clinicaltrial data, there is no suggestion that this medicinal product causes an adverse reaction on cardiaccontractility. However, this medicinal product has not been studied in patients with abnormal leftventricular ejection fraction (LVEF) or those with significant cardiac history. In patients with cardiacrisk factors and those with conditions that can affect LVEF, cardiac monitoring, including anassessment of LVEF at baseline and during treatment, should be considered. In patients who developrelevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessmentshould be considered.

In patients with an ejection fraction below the institution’s lower limit of normal, cardiac consultationas well as treatment interruption or discontinuation should be considered.

P-glycoprotein (P-gp) interactions

Concomitant treatment with strong inducers of P-gp may decrease exposure to afatinib(see section 4.5).

This medicinal product contains lactose. Patients with rare hereditary conditions of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

Interactions with drug transport systems

Effects of P-gp and breast cancer resistance protein (BCRP) inhibitors on afatinib

In vitro studies have demonstrated that afatinib is a substrate of P-gp and BCRP. When the strong P-gpand BCRP inhibitor ritonavir (200 mg twice a day for 3 days) was administered 1 hour before a singledose of 20 mg GIOTRIF, exposure to afatinib increased by 48% (area under the curve (AUC0-∞)) and39% (maximum plasma concentration (Cmax)). In contrast, when ritonavir was administeredsimultaneously or 6 hours after 40 mg GIOTRIF, the relative bioavailability of afatinib was119% (AUC0-∞) and 104% (Cmax) and 111% (AUC0-∞) and 105% (Cmax), respectively. Therefore, it isrecommended to administer strong P-gp inhibitors (including but not limited to ritonavir,cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus,nelfinavir, saquinavir, and amiodarone) using staggered dosing, preferably 6 hours or 12 hours apartfrom GIOTRIF (see section 4.2).

Effects of P-gp inducers on afatinib

Pre-treatment with rifampicin (600 mg once daily for 7 days), a potent inducer of P-gp, decreased theplasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) after administration of a single dose of40 mg GIOTRIF. Strong P-gp inducers (including but not limited to rifampicin, carbamazepine,phenytoin, phenobarbital or St. John’s wort (Hypericum perforatum)) may decrease exposure toafatinib (see section 4.4).

Effects 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 isconsidered unlikely that GIOTRIF treatment will result in changes of the plasma concentrations ofother P-gp substrates.

Interactions with BCRP

In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP. Afatinibmay increase the bioavailability of orally administered BCRP substrates (including but not limited torosuvastatin and sulfasalazine).

Food effect on afatinib

Co-administration of a high-fat meal with GIOTRIF resulted in a significant decrease of exposure toafatinib by about 50% in regard to Cmax and 39% in regard to AUC0-∞. This medicinal product shouldbe administered without food (see sections 4.2 and 5.2).

As a precautionary measure, women of childbearing potential should be advised to avoid becomingpregnant while receiving treatment with GIOTRIF. Adequate contraceptive methods should be usedduring therapy and for at least 1 month after the last dose.

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

Animal studies with afatinib did not indicate direct or indirect harmful effects with respect toreproductive toxicity (see section 5.3). Studies in animals have shown no signs of teratogenicity up toand including maternally lethal dose levels. Adverse changes were restricted to toxic dose levels.

However, systemic exposures achieved in animals were either in a similar range or below the levelsobserved in patients (see section 5.3).

There are no or limited amount of data from the use of this medicinal product in pregnant women. Therisk for humans is thus unknown. If used during pregnancy or if the patient becomes pregnant while orafter receiving GIOTRIF, she should be informed of the potential hazard to the foetus.

Available pharmacokinetic data in animals have shown excretion of afatinib in milk (see section 5.3).

Based on this, it is likely that afatinib is excreted in human milk. A risk to the breast-feeding childcannot be excluded. Mothers should be advised against breast-feeding while receiving this medicinalproduct.

Fertility studies in humans have not been performed with afatinib. Available non-clinical toxicologydata have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of thismedicinal product on human fertility cannot be excluded.

GIOTRIF has minor influence on the ability to drive and use machines. During treatment, ocularadverse reactions (conjunctivitis, dry eye, keratitis) have been reported in some patients(see section 4.8) which may affect patients ability to drive or use machines.

The types of adverse reactions (ADRs) were generally associated with the EGFR inhibitory mode ofaction of afatinib. The summary of all ADRs is shown in Table 2. The most frequent ADRs werediarrhoea and skin related adverse events (see section 4.4) as well as stomatitis and paronychia(see also Table 3, 4 and 5). Overall, dose reduction (see section 4.2) led to a lower frequency ofcommon adverse reactions.

In patients treated with once daily GIOTRIF 40 mg, dose reductions due to ADRs occurred in 57% ofthe patients in the LUX-Lung 3 trial and in 25% of the patients in the LUX-Lung 8 trial.

Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0% in LUX-Lung 3 and 3.8%and 2.0% in LUX-Lung 8, respectively.

ILD-like adverse reactions were reported in 0.7% of afatinib treated patients. Bullous, blistering andexfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnsonsyndrome and toxic epidermal necrolysis although in these cases there were potential alternativeaetiologies (see section 4.4).

Table 2 summarises the frequencies of ADRs from all NSCLC trials and from post-marketingexperience with daily GIOTRIF doses of 40 mg or 50 mg as monotherapy. The following terms areused to rank the ADRs by frequency: 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 frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Summary of ADRs per frequency category

Body System Very Common Uncommon Rarecommon

Infections and Paronychia1 Cystitisinfestations

Metabolism and nutrition Decreased Dehydrationdisorders appetite Hypokalaemia

Nervous system disorders Dysgeusia

Eye disorders Conjunctivitis Keratitis

Dry eye Aberranteyelash growth

Respiratory, thoracic and Epistaxis Rhinorrhoea Interstitial lungmediastinal disorders disease

Gastrointestinal disorders Diarrhoea Dyspepsia Pancreatitis

Stomatitis2 Cheilitis Gastrointestinal

Nausea perforation

Hepatobiliary disorders Alanineaminotransferaseincreased

Aspartateaminotransferaseincreased

Skin and subcutaneous Rash3 Palmar-plantar Stevens-Johnsontissue disorders Dermatitis erythrodysaesthesia syndrome7acneiform4 syndrome Toxic epidermal

Pruritus5 Nail disorders8 necrolysis7

Dry skin6

Musculoskeletal and Muscle spasmsconnective tissuedisorders

Renal and urinary Renal impairment/disorders Renal failure

General disorders and Pyrexiaadministration siteconditions

Investigations Weight decreased1 Includes Paronychia, Nail infection, Nail bed infection2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion,

Mucosal erosion, Mucosal ulceration3 Includes group of rash preferred terms4 Includes Acne, Acne pustular, Dermatitis acneiform5 Includes Pruritus, Pruritus generalised6 Includes Dry skin, Skin chapped7 Based on post-marketing experience8 Includes Nail disorder, Onycholysis, Nail toxicity, Onychoclasis, Ingrowing nail, Nail pitting, Onychomadesis,

Nail discoloration, Nail dystrophy, Nail ridging, and Onychogryphosis

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

LUX-Lung 3 and LUX-Lung 7 are summarised by National Cancer Institute-Common Toxicity

Criteria (NCI-CTC) Grade in Tables 3 and 4.

Table 3: Very common ADRs in trial LUX-Lung 3

GIOTRIF Pemetrexed/(40 mg/day) Cisplatin

N = 229 N = 111

NCI-CTC Grade Any 3 4 Any 3 4

Grade Grade

MedDRA Preferred Term % % % % % %

Paronychia1 57.6 11.4 0 0 0 0

Decreased appetite 20.5 3.1 0 53.2 2.7 0

Epistaxis 13.1 0 0 0.9 0.9 0

Diarrhoea 95.2 14.4 0 15.3 0 0

Stomatitis2 69.9 8.3 0.4 13.5 0.9 0

Cheilitis 12.2 0 0 0.9 0 0

Rash3 70.3 14 0 6.3 0 0

Dermatitis acneiform4 34.9 2.6 0 0 0 0

Dry skin5 29.7 0.4 0 1.8 0 0

Pruritus6 19.2 0.4 0 0.9 0 0

Weight decreased 10.5 0 0 9.0 0 01 Includes Paronychia, Nail infection, Nail bed infection2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion,

Mucosal erosion, Mucosal ulceration3 Includes group of rash preferred terms4 Includes Acne, Acne pustular, Dermatitis acneiform5 Includes Dry skin, Skin chapped6 Includes Pruritus, Pruritus generalised

Table 4: Very common ADRs in trial LUX-Lung 7

GIOTRIF Gefitinib(40 mg/day)

N = 160 N = 159

NCI-CTC Grade Any 3 4 Any 3 4

Grade Grade

MedDRA Preferred Term % % % % % %

Paronychia1 57.5 1.9 0 17.0 0.6 0

Cystitis2 11.3 1.3 0 7.5 1.3 0.6

Decreased appetite 27.5 1.3 0 24.5 1.9 0

Hypokalaemia3 10.6 2.5 1.3 5.7 1.3 0

Rhinorrhoea4 19.4 0 0 7.5 0 0

Epistaxis 18.1 0 0 8.8 0 0

Diarrhoea 90.6 13.8 0.6 64.2 3.1 0

Stomatitis5 64.4 4.4 0 27.0 0 0

Nausea 25.6 1.3 0 27.7 1.3 0

Vomiting 19.4 0.6 0 13.8 2.5 0

Dyspepsia 10.0 0 0 8.2 0 0

Alanine aminotransferase increased 11.3 0 0 27.7 8.8 0.6

Rash6 80.0 7.5 0 67.9 3.1 0

Dry skin 32.5 0 0 39.6 0 0

Pruritus7 25.6 0 0 25.2 0 0

Dermatitis acneiform8 23.8 1.9 0 32.1 0.6 0

Pyrexia 13.8 0 0 6.3 0 0

Weight decreased 10.0 0.6 0 5.7 0.6 01 Includes Paronychia, Nail infection, Nail bed infection2 Includes Cystitis, Urinary tract infection3 Includes Hypokalaemia, Blood potassium decreased4 Includes Rhinorrhoea, Nasal inflammation5 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Mucosal erosion6 Includes group of rash preferred terms7 Includes Pruritus, Pruritus generalised8 Includes Dermatitis acneiform, Acne

Liver function test abnormalities

Liver function test abnormalities (including elevated ALT and AST) were observed in patientsreceiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation.

Grade 2 (> 2.5 to 5.0 times upper limit of normal (ULN)) ALT elevations occurred in < 8% of patientstreated with this medicinal product. Grade 3 (> 5.0 to 20.0 times ULN) elevations occurred in < 4% ofpatients treated with GIOTRIF (see section 4.4).

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

LUX-Lung 8 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC)

Grade in Table 5.

Table 5: Very common ADRs in trial LUX-Lung 8*

GIOTRIF Erlotinib(40 mg/day)

N = 392 N = 395

NCI-CTC Grade Any 3 4 Any 3 4

Grade Grade

MedDRA Preferred Term % % % % % %

Paronychia1 11.0 0.5 0 5.1 0.3 0

Decreased appetite 24.7 3.1 0 26.1 2.0 0

Diarrhoea 74.7 9.9 0.8 41.3 3.0 0.3

Stomatitis2 30.1 4.1 0 10.6 0.5 0

Nausea 20.7 1.5 0 16.2 1.0 0.3

Rash3 60.7 5.4 0 56.7 8.1 0

Dermatitis acneiform4 14.0 1.3 0 18.0 2.5 0

* Reporting the frequency of patients with all causality AEs1 Includes Paronychia, Nail infection, Nail bed infection2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion,

Mucosal erosion, Mucosal ulceration3 Includes group of rash preferred terms4 Includes Acne, Acne pustular, Dermatitis acneiform

Liver function test abnormalities

Liver function test abnormalities (including elevated ALT and AST) were observed in patientsreceiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation.

Grade 2 ALT elevations occurred in 1% and Grade 3 elevations occurred in 0.8% of patients treatedwith GIOTRIF (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose of afatinib studied in a limited number of patients in Phase I clinical trials was160 mg once daily for 3 days and 100 mg once daily for 2 weeks. The adverse reactions observed atthese doses were primarily dermatological (rash/acne) and gastrointestinal events (especiallydiarrhoea). Overdose in 2 healthy adolescents involving the ingestion of 360 mg each of afatinib(as part of a mixed drug ingestion) was associated with adverse events of nausea, vomiting, asthenia,dizziness, headache, abdominal pain and elevated amylase (< 1.5 times ULN). Both individualsrecovered from these adverse events.

There is no specific antidote for overdose with this medicinal product. In cases of suspected overdose,

GIOTRIF should be withheld and supportive care initiated.

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

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

Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to andirreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members

EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.

Aberrant ErbB signalling triggered by receptor mutations, and/or amplification, and/or receptor ligandoverexpression contributes to the malignant phenotype. Mutation in EGFR defines a distinct molecularsubtype of lung cancer.

In non-clinical disease models with ErbB pathway deregulation, afatinib as a single agent effectivelyblocks ErbB receptor signalling resulting in tumour growth inhibition or tumour regression. NSCLCtumours with common activating EGFR mutations (Del 19, L858R) and several less common EGFRmutations in exon 18 (G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment innon-clinical and clinical settings. Limited non-clinical and/or clinical activity was observed in NSCLCtumours with insertion mutations in exon 20.

The acquisition of a secondary T790M mutation is a major mechanism of acquired resistance toafatinib and gene dosage of the T790M-containing allele correlates with the degree of resistancein vitro. The T790M mutation is found in approximately 50% of patients’ tumours upon diseaseprogression on afatinib, for which T790M targeted EGFR TKIs may be considered as a next linetreatment option. Other potential mechanisms of resistance to afatinib have been suggestedpreclinically and MET gene amplification has been observed clinically.

GIOTRIF in patients with Non-Small Cell Lung Cancer (NSCLC) with EGFR mutations

LUX-Lung 3

In the first-line setting, the efficacy and safety of GIOTRIF in patients with EGFR mutation-positivelocally advanced or metastatic NSCLC (stage IIIB or IV) were assessed in a global, randomised,multicentre, open-label trial. Patients were screened for the presence of 29 different EGFR mutationsusing a polymerase chain reaction (PCR)-based method (TheraScreen®: EGFR29 Mutation Kit,

Qiagen Manchester Ltd). Patients were randomised (2:1) to receive GIOTRIF 40 mg once daily or upto 6 cycles of pemetrexed/cisplatin. Among the patients randomised, 65% were female, the medianage was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were

Caucasian and 72% were Asian. 89% of patients had common EGFR mutations (Del 19 or L858R).

The primary endpoint was progression free survival (PFS) by independent review; the secondaryendpoints included overall survival and objective response rate. At the time of the analysis,14 Nov 2013, 176 patients (76.5%) in the afatinib arm and 70 patients (60.9%) in the chemotherapyarm experienced an event contributing to the PFS analysis, i.e. disease progression as determined bycentral independent review or death. The efficacy results are provided in Figure 1, Tables 6 and 7.

LUX-Lung 6

The efficacy and safety of GIOTRIF in Asian patients with Stage IIIB/IV EGFR mutation-positivelocally advanced or metastatic adenocarcinoma of the lung was evaluated in a randomised,multicentre, open-label trial. Similar to LUX-Lung 3, patients with previously untreated NSCLC werescreened for EGFR mutations using TheraScreen®: EGFR29 Mutation Kit (Qiagen Manchester Ltd).

Among randomized patients, 65% were female, the median age was 58 years and all patients were of

Asian ethnicity. Patients with common EGFR mutations accounted for 89% of the study population.

The primary endpoint was PFS as assessed by central independent review; secondary endpointsincluded OS and ORR.

Both trials demonstrated significant improvement in PFS of EGFR mutation positive patients treatedwith GIOTRIF compared to chemotherapy. The efficacy results are summarized in Figure 1(LUX-Lung 3) and Tables 6 and 7 (LUX-Lung 3 and 6). Table 7 shows outcomes in the subgroups ofpatients with two common EGFR mutations - Del 19 and L858R.

Figure 1: Kaplan-Meier curve for PFS by independent review by treatment group in trial LUX-Lung 3(Overall Population)

Table 6: Efficacy results of GIOTRIF vs. pemetrexed/cisplatin (LUX-Lung 3) gemcitabine/cisplatin(LUX-Lung 6) (Independent review)

LUX-Lung 3 LUX-Lung 6

GIOTRIF Pemetrexed/ GIOTRIF Gemcitabine/

Cisplatin Cisplatin(N = 230) (N = 115) (N = 242) (N = 122)

Progression-free survival 11.2 6.9 11 .0 5.6

Months (median)

Hazard Ratio (HR) 0.58 0.28(95%CI) (0.43-0.78) (0.20-0.39)p-value1 0.0002 < 0.00011-year PFS Rate 48.1% 22.0% 46.7% 2.1%

Objective Response Rate(CR+PR)2 56.5% 22.6% 67.8% 23.0%

Odds Ratio (OR) 4.80 7.57(95%CI) (2.89-8.08) (4.52-12.68)p-value1 < 0.0001 < 0.0001

Overall Survival (OS) 28.2 28.2 23.1 23.5

Months (median)

Hazard Ratio (HR) 0.88 0.93(95%CI) (0.66-1.17) (0.72-1.22)p-value1 0.3850 0.61371 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logisticregression2 CR = complete response; PR = partial response

Table 7: PFS and OS efficacy results of GIOTRIF vs pemetrexed/cisplatin (LUX-Lung 3)gemcitabine/cisplatin (LUX-Lung 6) in the pre-defined EGFR mutation subgroups Del 19 and L858R(Independent review)

LUX-Lung 3 LUX-Lung 6

GIOTRIF Pemetrexed/ GIOTRIF Gemcitabine/

Del19 Cisplatin Cisplatin(N = 112) (N = 57) (N = 124) (N = 62)

Progression-free survival 13.8 5.6 13.1 5.6

Months (median)

Hazard Ratio (HR) 0.26 0.20(95%CI) (0.17-0.42) (0.13-0.33)p-value1 < 0.0001 < 0.0001

Overall Survival (OS) 33.3 21.1 31.4 18.4

Months (median)

Hazard Ratio (HR) 0.54 0.64(95%CI) (0.36-0.79) (0.44-0.94)p-value1 0.0015 0.0229

GIOTRIF Pemetrexed/ GIOTRIF Gemcitabine/

L858R Cisplatin Cisplatin(N = 91) (N = 47) (N = 92) (N = 46)

Progression-free survival 10.8 8.1 9.6 5.6

Months (median)

Hazard Ratio (HR) 0.75 0.31(95%CI) (0.48-1.19) (0.19-0.52)p-value1 0.2191 < 0.0001

Overall Survival (OS) 27.6 40.3 19.6 24.3

Months (median)

Hazard Ratio (HR) 1.30 1.22(95%CI) (0.80-2.11) (0.81-1.83)p-value1 0.2919 0.34321 p-value for PFS/OS based on stratified log-rank test

In the pre-defined subgroup of common mutations (combined Del 19 and L858R) for GIOTRIF andchemotherapy, the median PFS was 13.6 months vs. 6.9 months (HR 0.48; 95%

CI 0.35-0.66; p < 0.0001; N = 307) in LUX-Lung 3, and 11.0 months vs. 5.6 months (HR 0.24; 95%

CI 0.17-0.35; p < 0.0001; N = 324) in LUX-Lung 6, respectively.

PFS benefit was accompanied by improvement in disease-related symptoms and delayed time todeterioration (see Table 8). Mean scores over time for overall quality of life, global health status andphysical, role, cognitive, social and emotional functioning were significantly better for GIOTRIF.

Table 8: Symptom outcomes for GIOTRIF vs. chemotherapy in trials LUX-Lung 3 and LUX-Lung 6(EORTC QLQ-C30 & QLQ-LC13)

LUX-L ung 3

Cough Dyspnoea Pain% of patients improved a 67% vs. 60%; 65% vs. 50%; 60% vs. 48%;p = 0.2133 p = 0.0078 p = 0.0427

Delay of median time to 27.0 vs. 8.0 10.4 vs. 2.9 4.2 vs. 3.1deterioration (months) a,b HR 0.60; p = 0.0062 HR 0.68; p = 0.0129 HR 0.83; p = 0.1882

LUX-L ung 6

Cough Dyspnoea Pain% of patients improved a 76% vs. 55%; 71% vs. 48%; 65% vs. 47%;p = 0.0003 p < 0.0001 p = 0.0017

Delay of median time to 31.1 vs. 10.3 7.7 vs. 1.7 6.9 vs. 3.4deterioration (months) a,b HR 0.46; p = 0.0001 HR 0.53; p < 0.0001 HR 0.70; p = 0.0220a values presented for GIOTRIF vs. chemotherapy, p-value based on logistic regressionb p-value for time to deterioration based on stratified log-rank test

LUX-Lung 2

LUX-Lung 2 was a single arm Phase II trial in 129 EGFR TKI-naïve patients with stage IIIB or IVlung adenocarcinoma with EGFR mutations. Patients were enrolled in the first-line (N = 61) orsecond-line setting (N = 68) (i.e. after failure of 1 prior chemotherapy regimen). In 61 patients treatedin the first-line setting, confirmed ORR was 65.6% and DCR was 86.9% according to independentreview. The median PFS was 12.0 months by independent review. Efficacy was similarly high in thegroup of patients who had received prior chemotherapy (N = 68; ORR 57.4%; median PFS byindependent review 8 months). The updated median OS for first- and second-line was 31.7 months and23.6 months, respectively.

LUX-Lung 7

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 EGFRmutations (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 hadbrain metastases, the baseline ECOG performance status was 0 (31%) or 1 (69%), 57% were Asianand 43% were non-Asian. Patients had a tumour sample with an EGFR mutation categorised as eitherexon 19 deletion (58%) or exon 21 L858R substitutions (42%).

The co-primary endpoints include PFS by independent review and OS. Secondary endpoints include

ORR and DCR. GIOTRIF significantly improved PFS and ORR in EGFR mutation positive patientscompared to gefitinib. The efficacy results are summarized in Table 9.

Table 9: Efficacy results of GIOTRIF vs. gefitinib (LUX-Lung 7) based on primary analysis as of

August 2015.

GIOTRIF Gefitinib Hazard Ratio/(N = 160) (N = 159) Odds Ratio(95%CI)p-value2

Median PFS (months), Overall 11.0 10.9 HR 0.73

Trial Population (0.57-0.95)0.016518-months PFS rate 27% 15%24-months PFS rate 18% 8%

Median OS (months)1, Overall 27.9 24.5 HR 0.86

Trial Population (0.66, 1.12)0.2580

Alive at 18-months 71% 67%

Alive at 24-months 61% 51%

Objective Response Rate 70% 56% OR 1.87(CR+PR)3 (1.12, 2.99)0.00831 OS results based on primary OS analysis as of April 2016 at event rates of 109 (68.1%) and 117 (73.6%) in the

GIOTRIF and gefitinib arms, respectively2 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on stratifiedlogistic regression3 CR = complete response; PR = partial response

The PFS hazard ratio for patients with DEL 19 mutations and L858R mutations was 0.76 (95% CI[0.55, 1.06]; p = 0.1071), and 0.71 (95% CI [0.47, 1.06]; p = 0.0856) respectively for afatinib vsgefitinib.

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 3and -6, and single arm Phase 2 trial LUX-Lung 2), an analysis was conducted of data from a total of75 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 patients with tumours harbouring either G719X (N = 18), L861Q (N = 16), or S768I substitutionmutation (N = 8), the confirmed ORR was 72.2%, 56.3%, 75.0%, respectively, and the medianduration of response was 13.2 months, 12.9 months and 26.3 months, respectively.

In patients with tumours harbouring exon 20 insertions (N = 23) the confirmed ORR was 8.7% and themedian duration of response was 7.1 months. In patients with tumours harbouring de-novo T790Mmutations (N = 14) the confirmed ORR was 14.3% and the median duration of response was8.3 months.

GIOTRIF in patients with NSCLC of squamous histology

The efficacy and safety of GIOTRIF as second-line treatment for patients with advanced NSCLC ofsquamous histology was investigated in a randomized 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 weresubsequently randomized 1:1 to daily GIOTRIF 40 mg or erlotinib 150 mg until progression.

Randomization was stratified by race (Eastern Asian vs non Eastern Asian). The primary endpoint was

PFS; OS was the key secondary endpoint. Other secondary endpoints included ORR, DCR, change intumour size and HRQOL.

Among 795 patients randomized, the majority were males (84%), white (73%), current or formersmokers (95%) with baseline performance status ECOG 1 (67%) and ECOG 0 (33%).

Second-line GIOTRIF significantly improved PFS and OS of patients with squamous NSCLCcompared to erlotinib. The efficacy results at the time of the primary analysis of OS including allrandomized patients are summarized in Figure 2 and Table 10.

Table 10: Efficacy results for GIOTRIF vs erlotinib in LUX-Lung 8, based on primary analysis of OS,including all randomized patients

GIOTRIF Erlotinib Hazard Ratio/ p-value2

Odds Ratio(N = 398) (n = 397) (95%CI)

PFS

Months (median) 2.63 1.94 HR 0.81 0.0103(0.69, 0.96)

OS

Months (median) 7.92 6.77 HR 0.81 0.0077(0.69, 0.95)

Alive at 12 months 36.4% 28.2%

Alive at 18 months 22.0% 14.4%

Objective Response 5.5% 2.8% OR 2.06 0.0551

Rate (CR+PR)1 (0.98, pct. 4.32)

Duration of response 7.29 3.71

Months (median)1 CR=complete response; PR=partial response2 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logisticregression

The overall survival hazard ratio in patients < 65 years of age was 0.68 (95% CI 0.55, 0.85) and inpatients 65 years of age and older it was 0.95 (95% CI 0.76, 1.19).

Figure 2: Kaplan-Meier Curve for OS by treatment group in LUX-Lung 8

PFS benefit was accompanied by improvement in disease-related symptoms and delayed time todeterioration (see Table 11).

Table 11: Symptom outcomes for GIOTRIF vs. erlotinib in trial LUX-Lung 8 (EORTC QLQ-C30 &

QLQ-LC13)

Cough Dyspnoea Pain% of patients 43% vs. 35%; 51% vs. 44%; 40% vs. 39%;improveda, c p = 0.0294 p = 0.0605 p = 0.7752

Delay of time to 4.5 vs. 3.7 2.6 vs. 1.9 2.5 vs. 2.4deterioration HR 0.89; p = 0.2562 HR 0.79; p = 0.0078 HR 0.99; p = 0.8690(months)b, ca values presented for GIOTRIF vs. erlotinib, p-value based on logistic regressionb p-value for time to deterioration based on stratified log-rank testc p-values were not adjusted for multiplicity

Efficacy in EGFR-negative tumours has not been established.

The European Medicines Agency has waived the obligation to submit the results of trials with thismedicinal product in all subsets of the paediatric population in NSCLC indications (see section 4.2 forinformation on paediatric use). However, paediatric development was conducted in paediatric patientswith other conditions.

A Phase I/II open-label, dose escalation, multicentre trial evaluated the safety and efficacy of

GIOTRIF in paediatric patients aged 2 to less than 18 years with recurrent/refractory neuroectodermaltumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulationregardless of tumour histology. A total of 17 patients were treated in the dose finding part of the trial.

In the maximum tolerated dose (MTD) expansion part of the trial, 39 patients selected by biomarkersfor ErbB pathway deregulation received GIOTRIF at a dose of 18 mg/m²/day. In this expansion part,no objective responses were observed in 38 patients, including 6 patients with refractory high gradeglioma (HGG), 4 patients with diffuse intrinsic pontine glioma (DIPG), 8 patients with ependymomaand 20 patients with other histologies. One patient with a neural-glial tumour of the brain with a

CLIP2-EGFR gene fusion had a confirmed partial response (see section 4.2 for information onpaediatric use). The adverse reaction profile of GIOTRIF in paediatric patients was consistent with thesafety profile seen in adults.

Following oral administration of GIOTRIF, Cmax of afatinib were observed approximately 2 to 5 hourspost dose. Cmax and AUC0-∞ values increased slightly more than proportionally in the dose range from20 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 to administration in the fasted state.

Based on population pharmacokinetic data derived from clinical trials in various tumour types, anaverage decrease of 26% in AUCτ,ss was observed when food was consumed within 3 hours beforeor 1 hour after taking GIOTRIF. Therefore, food should not be consumed for at least 3 hours beforeand at least 1 hour after taking GIOTRIF (see sections 4.2 and 4.5).

In vitro binding of afatinib to human plasma proteins is approximately 95%. Afatinib binds to proteinsboth non-covalently (traditional protein binding) and covalently.

Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts toproteins were the major circulating metabolites of afatinib.

In humans, excretion of afatinib is primarily via the faeces. Following administration of an oralsolution of 15 mg afatinib, 85.4% of the dose was recovered in the faeces and 4.3% in urine. Theparent compound afatinib accounted for 88% of the recovered dose. Afatinib is eliminated with aneffective half-life of approximately 37 hours. Thus, steady state plasma concentrations of afatinib wereachieved within 8 days of multiple dosing of afatinib resulting in an accumulation of 2.77-fold(AUC0-∞) and 2.11-fold (Cmax). In patients treated with afatinib for more than 6 months a terminalhalf-life of 344 h was estimated.

Less than 5% of a single dose of afatinib is excreted via the kidneys. Exposure to afatinib in subjectswith renal impairment was compared to healthy volunteers following a single dose of 40 mg

GIOTRIF. Subjects with moderate renal impairment (n = 8; eGFR 30-59 mL/min/1.73 m², accordingto the Modification of Diet in Renal Disease [MDRD] formula) had an exposure of 101% (Cmax) and122% (AUC0-tz) in comparison to their healthy controls. Subjects with severe renal impairment(n = 8; eGFR 15-29 mL/min/1.73 m², according to the MDRD formula) had an exposure of 122%(Cmax) and 150% (AUC0-tz) in comparison to their healthy controls. Based on this trial and populationpharmacokinetic analysis of data derived from clinical trials in various tumour types, it is concluded,that adjustments to the starting dose in patients with mild (eGFR 60-89 mL/min/1.73 m²), moderate(eGFR 30-59 mL/min/1.73 m²), or severe (eGFR 15-29 mL/min/1.73 m²) renal impairment are notnecessary, but patients with severe impairment should be monitored (see “Population pharmacokineticanalysis in special populations” below and section 4.2). GIOTRIF has not been studied in patients witheGFR < 15 mL/min/1.73 m² or on dialysis.

Afatinib is eliminated mainly by biliary/faecal excretion. Subjects with mild (Child Pugh A) ormoderate (Child Pugh B) hepatic impairment had similar exposure in comparison to healthyvolunteers following a single dose of 50 mg GIOTRIF. This is consistent with populationpharmacokinetic data derived from clinical trials in various tumour types (see “Populationpharmacokinetic analysis in special populations” below). No starting dose adjustments appearnecessary in patients with mild or moderate hepatic impairment (see section 4.2). Thepharmacokinetics of afatinib have not been studied in subjects with severe (Child Pugh C) hepaticdysfunction (see section 4.4).

Population pharmacokinetic analysis in special populations

A population pharmacokinetic analysis was performed in 927 cancer patients (764 with NSCLC)receiving GIOTRIF monotherapy. No starting dose adjustment was considered necessary for any ofthe following covariates tested.

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

Plasma exposure (AUCτ,ss) was increased by 26% for a 42 kg patient (2.5th percentile) and decreasedby 22% for a 95 kg patient (97.5th percentile) relative to a patient weighing 62 kg (median body weightof patients in the overall patient population).

Female patients had a 15% higher plasma exposure (AUCτ,ss, body weight corrected) than malepatients.

Race had no effect on the pharmacokinetics of afatinib based on a population pharmacokineticanalysis, including patients of Asian, White, and Black racial groups. Data on Black racial groups waslimited.

Exposure to afatinib moderately increased with lowering of the creatinine clearance (CrCL, calculatedaccording to Cockcroft Gault), i.e. for a patient with a CrCL of 60 mL/min or 30 mL/min exposure(AUCτ,ss) to afatinib increased by 13% and 42%, respectively, and decreased by 6% and 20% for apatient with CrCL of 90 mL/min or 120 mL/min, respectively, compared to a patient with the CrCL of79 mL/min (median CrCL of patients in the overall patient population analysed).

Patients with mild and moderate hepatic impairment as identified by abnormal liver tests did notcorrelate with any significant change in afatinib exposure. There was limited data available formoderate and severe hepatic impairment.

Other patient characteristics/intrinsic factors

Other patient characteristics/intrinsic factors found with a significant impact on afatinib exposurewere: ECOG performance score, lactate dehydrogenase levels, alkaline phosphatase levels and totalprotein. The individual effect sizes of these covariates were considered not clinically relevant.

Smoking history, alcohol consumption (limited data), or presence of liver metastases had nosignificant impact on the pharmacokinetics of afatinib.

After administration of 18 mg/m2 afatinib, the steady-state exposure (AUC and Cmax) in paediatricpatients aged 2 to less than 18 years was comparable to that observed in adults given 40-50 mgafatinib (see also section 4.2 for information on paediatric use).

Other information on drug-drug interactions

Interactions with 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.

Interactions with Cytochrome P450 (CYP) enzymes

In humans it was found that enzyme-catalyzed metabolic reactions play a negligible role for themetabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3 and the

CYP3A4-dependent N-demethylation was too low to be quantitatively detected. Afatinib is not aninhibitor or an inducer of CYP enzymes. Therefore, this medicinal product is unlikely to interact withother medicines that modulate or are metabolised by CYP enzymes.

Effect of UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibition on afatinib

In vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 areconsidered unlikely.

Oral administration of single doses to mice and rats indicated a low acute toxic potential of afatinib. Inoral repeated-dose studies for up to 26 weeks in rats or 52 weeks in minipigs the main effects wereidentified in the skin (dermal changes, epithelial atrophy and folliculitis in rats), the gastrointestinaltract (diarrhoea, erosions in the stomach, epithelial atrophy in rats and minipigs) and the kidneys(papillary necrosis in rats). Depending on the finding, these changes occurred at exposures below, inthe range of or above clinically relevant levels. Additionally, in various organs pharmacodynamicallymediated atrophy of epithelia was observed in both species.

Reproduction toxicity

Based on the mechanism of action, all EGFR targeting medicinal products including GIOTRIF havethe potential to cause foetal harm. The embryo-foetal development studies performed on afatinibrevealed no indication of teratogenicity. The respective total systemic exposure (AUC) was eitherslightly above (2.2 times in rats) or below (0.3 times in rabbits) compared with levels in patients.

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

A fertility study in male and female rats up to the maximum tolerated dose revealed no significantimpact on fertility. The total systemic exposure (AUC0-24) in male and female rats was in the range orless than that observed in patients (1.3 times and 0.51 times, respectively).

A study in rats up to the maximum tolerated doses revealed no significant impact on pre-/postnataldevelopment. The highest total systemic exposure (AUC0-24) in female rats was less than that observedin patients (0.23 times).

An in vitro 3T3 test showed that afatinib may have phototoxicity potential.

Carcinogenicity studies have not been conducted with GIOTRIF.

Lactose monohydrate

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous (E551)

Crospovidone (type A)

Magnesium stearate (E470b)

GIOTRIF 20 mg film-coated tablets

Hypromellose (E464)

Macrogol 400

Titanium dioxide (E171)

Talc (E553b)

Polysorbate 80 (E433)

GIOTRIF 30, 40 and 50 mg film-coated tablets

Hypromellose (E464)

Macrogol 400

Titanium dioxide (E171)

Talc (E553b)

Polysorbate 80 (E433)

Indigo carmine aluminium lake (E132)

Not applicable.

3 years.

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

PVC/PVDC perforated unit dose blister. Each blister is packed together with a desiccant sachet in alaminated aluminium pouch and contains 7 × 1 film-coated tablets. Pack sizes of 7 × 1, 14 × 1 or28 × 1 film-coated tablets.

Not all pack sizes may be marketed.

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

Boehringer Ingelheim International GmbH

Binger Strasse 17355216 Ingelheim am Rhein

Germany

GIOTRIF 20 mg film-coated tablets

EU/1/13/879/001

EU/1/13/879/002

EU/1/13/879/003

GIOTRIF 30 mg film-coated tablets

EU/1/13/879/004

EU/1/13/879/005

EU/1/13/879/006

GIOTRIF 40 mg film-coated tablets

EU/1/13/879/007

EU/1/13/879/008

EU/1/13/879/009

GIOTRIF 50 mg film-coated tablets

EU/1/13/879/010

EU/1/13/879/011

EU/1/13/879/012

Date of first authorisation: 25 September 2013

Date of latest renewal: 16 May 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu