Giotrif

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 20 mg film-coated tablets
GIOTRIF 30 mg film-coated tablets
GIOTRIF 40 mg film-coated tablets
GIOTRIF 50 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

GIOTRIF 20 mg film-coated tablets
One film-coated tablet contains 20 mg afatinib (as dimaleate).
Excipient with known effect
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.

3. PHARMACEUTICAL FORM

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

GIOTRIF 40 mg film-coated tablets
Light blue, round, biconvex and bevel-edged film-coated tablet debossed with the code “T40” on one side 
and the Boehringer Ingelheim company logo on the other.

GIOTRIF 50 mg film-coated tablets
Dark blue, oval, biconvex film-coated tablet debossed with the code “T50” on one side and the Boehringer 
Ingelheim company logo on the other.



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4. CLINICAL PARTICULARS

4.1 Therapeutic indications

GIOTRIF as monotherapy is indicated for the treatment of 
 Epidermal Growth Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced or 

metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s);
 Adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or 

after platinum-based chemotherapy (see section 5.1).

4.2 Posology and method of administration

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

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

Posology
The recommended dose is 40 mg once daily.

This medicinal product should be taken without food. Food should not be consumed for at least 3 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 the patient 
(see Table 1 below). 

Dose escalation
A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/day 
starting dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE 
Grade > 1) in the first cycle of treatment (21 days for EGFR mutation positive NSCLC and 28 days for 
squamous NSCLC). The dose should not be escalated in any patients with a prior dose reduction. The 
maximum daily dose is 50 mg.

Dose adjustment for adverse reactions
Symptomatic adverse reactions (e.g. severe/persistent diarrhoea or skin related adverse reactions) may be 
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
Grade > 3

Interrupt  until 
Grade 0/1 b

Resume with dose 
reduction by 10 mg 
decrements d

a NCI Common Terminology Criteria for Adverse Events 
b In case of diarrhoea, anti-diarrhoeal medicinal products (e.g. loperamide) should be taken immediately and 
continued for persistent diarrhoea until loose bowel movements cease.
c > 48 hours of diarrhoea and/or > 7 days of rash
d If patient cannot tolerate 20 mg/day, permanent discontinuation of GIOTRIF should be considered

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



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Missed dose
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-gp 
inhibitor dose should be taken as far apart in time as possible from the GIOTRIF dose. This means preferably 
6 hours (for P-gp inhibitors dosed twice daily) or 12 hours (for P-gp inhibitors dosed once daily) apart from
GIOTRIF (see section 4.5).

Special populations

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

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

Paediatric population
There is no relevant use of GIOTRIF in the paediatric population in the indication of NSCLC. Therefore, 
treatment of children or adolescents with this medicinal product is not recommended.

Method of administration
This medicinal product is for oral use. The tablets should be swallowed whole with water. If swallowing of 
whole tablets is not possible, these can be dispersed in approximately 100 ml of non-carbonated drinking 
water. No other liquids should be used. The tablet should be dropped into the water without crushing it, and 
stirred occasionally for up to 15 min until it 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

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

4.4 Special warnings and precautions for use

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

Diarrhoea
Diarrhoea, including severe diarrhoea, has been reported during treatment with GIOTRIF (see section 4.8). 
Diarrhoea may result in dehydration with or without renal impairment, which in rare cases 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. 



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Proactive management of diarrhoea including adequate hydration combined with anti-diarrhoeal medicinal 
products especially within the first 6 weeks of the treatment is important and should start at first signs of 
diarrhoea. Antidiarrhoeal medicinal products (e.g. loperamide) should be used and if necessary their dose 
should be escalated to the highest recommended approved dose. Anti-diarrhoeal medicinal products should 
be readily available to the patients so that treatment can be initiated at first signs of diarrhoea and continued 
until loose bowel movements cease for 12 hours. Patients with severe diarrhoea may require interruption and 
dose reduction or discontinuation of therapy with GIOTRIF (see section 4.2). Patients who become 
dehydrated may require administration of intravenous electrolytes and fluids. 

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

Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of 
Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment with this medicinal product should be 
interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions (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 and those 
with underlying renal impairment (see section 5.2). This could result in a higher risk of developing adverse 
reactions in particular 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 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 patients treated 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 pulmonary symptoms 
(dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with this medicinal 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). 

Severe hepatic impairment
Hepatic failure, including fatalities, has been reported during treatment with this medicinal product 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. In the pivotal trials Grade 3 alanine 
aminotransferase (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 with 40 mg/day. 
In LUX-Lung-3 Grade 3 ALT/AST elevations were about 3.5 fold higher in patients with abnormal baseline 
liver tests. There were no Grade 3 ALT/AST elevations in patients with abnormal baseline liver tests in 
LUX-Lung 8 (see section 4.8). Dose interruption may become necessary in patients who experience 
worsening of liver function (see section 4.2). In patients who develop severe hepatic impairment while taking 
GIOTRIF, treatment should be discontinued. 

Gastrointestinal perforations
Gastrointestinal perforation, including fatalities, has been reported during treatment with GIOTRIF in 0.2% 
of patients across all randomized controlled clinical trials. In the majority of cases, gastrointestinal 



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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 should be interrupted or discontinued. If keratitis is diagnosed, the benefits 
and risks of continuing treatment should be carefully considered. This medicinal product 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). 

Left ventricular function
Left ventricular dysfunction has been associated with HER2 inhibition. Based on the available clinical trial 
data, there is no suggestion that this medicinal product causes an adverse reaction on cardiac contractility. 
However, this medicinal product 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 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 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).

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

4.5 Interaction with other medicinal products and other forms of interaction

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-gp and 
BCRP inhibitor ritonavir (200 mg twice a day for 3 days) was administered 1 hour before a single dose of 
20 mg GIOTRIF, exposure to afatinib increased by 48% (area under the curve (AUC0-∞)) and 
39% (maximum plasma concentration (Cmax)). In contrast, when ritonavir was administered simultaneously 
or 6 hours after 40 mg GIOTRIF, the relative bioavailability of afatinib was 119% (AUC0-∞) and 
104% (Cmax) and 111% (AUC0-∞) and 105% (Cmax), respectively. Therefore, it is recommended 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 apart from 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 the plasma 
exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) after administration of a single dose of 40 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 to afatinib (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 is 
considered unlikely that GIOTRIF treatment will result in changes of the plasma concentrations of other 



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P-gp substrates.

Interactions with 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).

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
As a precautionary measure, 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 1 month after the last dose.

Pregnancy
Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm.
Animal studies with afatinib did not indicate direct or indirect harmful effects with respect to reproductive 
toxicity (see section 5.3). Studies in animals have shown no signs of teratogenicity up to and including 
maternally lethal dose levels. Adverse changes were restricted to toxic dose levels. However, systemic 
exposures achieved in animals were either in a similar range or below the levels observed in patients (see 
section 5.3). 

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

Breast-feeding
Available pharmacokinetic data in animals have shown excretion of afatinib in milk (see section 5.3). Based 
on this, it is likely that afatinib is excreted in human milk. A risk to the breast-feeding child cannot be 
excluded.  Mothers should be advised against breast-feeding while receiving this medicinal product.

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile
The types of adverse reactions (ADRs) were generally associated with the EGFR inhibitory mode of action 
of afatinib. The summary of all ADRs is shown in Table 2. The most frequent ADRs were diarrhoea 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 of common adverse reactions. 

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



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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 and 
exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome 
and toxic epidermal necrolysis although in these cases there were potential alternative aetiologies (see 
section 4.4).

Tabulated list of adverse reactions
Table 2 summarises the frequencies of ADRs from all NSCLC trials and from post-marketing experience 
with daily GIOTRIF doses of 40 mg or 50 mg as monotherapy. The following terms are used 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 frequency grouping, adverse reactions are 
presented in order of decreasing seriousness.

Table 2: Summary of ADRs per frequency category

Body System Very 
common

Common Uncommon Rare

Infections and 
infestations

Paronychia1 Cystitis

Metabolism and nutrition 
disorders

Decreased 
appetite

Dehydration
Hypokalaemia

Nervous system disorders Dysgeusia
Eye disorders Conjunctivitis

Dry eye
Keratitis

Respiratory, thoracic and 
mediastinal disorders

Epistaxis Rhinorrhoea Interstitial lung 
disease

Gastrointestinal disorders Diarrhoea
Stomatitis2

Nausea
Vomiting

Dyspepsia
Cheilitis

Pancreatitis
Gastrointestinal 
perforation

Hepatobiliary disorders Alanine 
aminotransferase 
increased

Aspartate 
aminotransferase 
increased

Skin and subcutaneous 
tissue disorders

Rash3

Dermatitis 
acneiform4

Pruritus5

Dry skin6

Palmar-plantar 
erythrodysaesthesia 
syndrome
Nail disorders8

Stevens-Johnson 
syndrome7

Toxic epidermal 
necrolysis7

Musculoskeletal and 
connective tissue 
disorders

Muscle spasms

Renal and urinary 
disorders

Renal impairment/
Renal failure

General disorders and 
administration site 
conditions

Pyrexia

Investigations Weight decreased
1 Includes Paronychia, Nail infection, Nail bed infection
2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, 
  Mucosal erosion, Mucosal ulceration 
3 Includes group of rash preferred terms



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4 Includes Acne, Acne pustular, Dermatitis acneiform
5 Includes Pruritus, Pruritus generalised
6 Includes Dry skin, Skin chapped
7 Based on post-marketing experience
8 Includes Nail disorder, Onycholysis, Nail toxicity, Onychoclasis, Ingrowing nail, Nail pitting, 
Onychomadesis, Nail discoloration, Nail dystrophy, Nail ridging, and Onychogryphosis

Description of selected adverse reactions
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
(40 mg/day)

N=229

Pemetrexed/
Cisplatin

N=111
NCI-CTC Grade Any 

Grade
3 4 Any 

Grade
3 4

MedDRA Preferred Term % % % % % %
Infections and infestations
     Paronychia1 57.6 11.4 0 0 0 0
Metabolism and nutrition disorders
     Decreased appetite 20.5 3.1 0 53.2 2.7 0
Respiratory, thoracic and mediastinal disorders
     Epistaxis 13.1 0 0 0.9 0.9 0
Gastrointestinal disorders
     Diarrhoea 95.2 14.4 0 15.3 0 0
     Stomatitis2

     Cheilitis
69.9
12.2

8.3
0

0.4
0

13.5
0.9

0.9
0

0
0

Skin and subcutaneous tissue disorders
     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
Investigations
    Weight decreased 10.5 0 0 9.0 0 0
1 Includes Paronychia, Nail infection, Nail bed infection
2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, 
  Mucosal erosion, Mucosal ulceration 
3 Includes group of rash preferred terms
4 Includes Acne, Acne pustular, Dermatitis acneiform
5 Includes Dry skin, Skin chapped
6 Includes Pruritus, Pruritus generalised



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

GIOTRIF
(40 mg/day)
N=160

Gefitinib

N=159
NCI-CTC Grade Any

Grade
3 4 Any

Grade
3 4

MedDRA Preferred Term % % % % % %
Infections and infestations
      Paronychia1 57.5 1.9 0 17.0 0.6 0
     Cystitis2 11.3 1.3 0 7.5 1.3 0.6

Metabolism and nutrition disorders
      Decreased appetite 27.5 1.3 0 24.5 1.9 0
      Hypokalaemia3 10.6 2.5 1.3 5.7 1.3 0
Respiratory, thoracic and mediastinal disorders
      Rhinorrhoea4 19.4 0 0 7.5 0 0
      Epistaxis 18.1 0 0 8.8 0 0
Gastrointestinal disorders
      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
Hepatobiliary disorders
      Alanine aminotransferase increased 11.3 0 0 27.7 8.8 0.6
Skin and subcutaneous tissue disorders
      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
General disorders and administration site conditions
      Pyrexia 13.8 0 0 6.3 0 0
Investigations
      Weight decreased 10.0 0.6 0 5.7 0.6 0
1 Includes Paronychia, Nail infection, Nail bed infection
2 Includes Cystitis, Urinary tract infection
3 Includes Hypokalaemia, Blood potassium decreased
4 Includes Rhinorrhoea, Nasal inflammation
5 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Mucosal erosion
6 Includes group of rash preferred terms
7 Includes Pruritus, Pruritus generalised
8 Includes Dermatitis acneiform, Acne

Liver function test abnormalities
Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving 
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 patients treated with this 
medicinal product. Grade 3 (> 5.0 to 20.0 times ULN) elevations occurred in <4% of patients treated with 
GIOTRIF (see section 4.4).

Description of selected adverse reactions
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. 



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

GIOTRIF
(40 mg/day)
N=392

Erlotinib
N=395

NCI-CTC Grade Any 
Grade

3 4 Any 
Grade

3 4

MedDRA Preferred Term % % % % % %

Infections and infestations
     Paronychia1 11.0 0.5 0 5.1 0.3 0

Metabolism and nutrition disorders
     Decreased appetite 24.7 3.1 0 26.1 2.0 0

Gastrointestinal disorders
     Diarrhoea 74.7 9.9 0.8 41.3 3.0 0.3
     Stomatitis2

     Nausea
30.1
20.7

4.1
1.5

0
0

10.6
16.2

0.5
1.0

0
0.3

Skin and subcutaneous tissue disorders
     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 AEs
1 Includes Paronychia, Nail infection, Nail bed infection
2 Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, 
  Mucosal erosion, Mucosal ulceration 
3 Includes group of rash preferred terms
4 Includes Acne, Acne pustular, Dermatitis acneiform

Liver function test abnormalities
Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving 
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 treated with GIOTRIF (see 
section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms
The highest dose of afatinib 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 these doses were 
primarily dermatological (rash/acne) and gastrointestinal events (especially diarrhoea). 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 individuals recovered from these adverse events. 

Treatment
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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE13.

Mechanism of action
Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and 
irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR 
(ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. 

Pharmacodynamic effects

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

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. NSCLC tumours with 
common activating EGFR mutations (Del 19, L858R) and several less common EGFR mutations in exon 18 
(G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment in non-clinical and clinical 
settings. Limited non-clinical and/or clinical activity was observed in NSCLC tumours with insertion 
mutations in exon 20.

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. Other potential mechanisms 
of resistance to afatinib have been suggested preclinically and MET gene amplification has been observed 
clinically.

Clinical efficacy and safety

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-positive locally 
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 mutations using 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 up to 6 cycles of 
pemetrexed/cisplatin. Among the patients randomised, 65% were female, the median age 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 secondary endpoints 
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 chemotherapy arm experienced an event 
contributing to the PFS analysis, i.e. disease progression as determined by central independent review or 
death. The efficacy results are provided in Figure 1, Tables 6 and 7.



13

LUX-Lung 6
The efficacy and safety of GIOTRIF in Asian patients with Stage IIIB/IV EGFR mutation-positive locally 
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 were screened 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 endpoints included OS 
and ORR. 
Both trials demonstrated significant improvement in PFS of EGFR mutation positive patients treated with 
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 of patients 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)



14

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

(N=230)

Pemetrexed/
Cisplatin
(N=115)

GIOTRIF

(N=242)

Gemcitabine/
Cisplatin
(N=122)

Progression-free survival 
Months (median) 

11.2 6.9 11.0 5.6

Hazard Ratio (HR)
(95%CI)

0.58
(0.43-0.78)

0.28
(0.20-0.39)

p-value1 0.0002 <0.0001
1-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)
(95%CI)

4.80
(2.89-8.08)

7.57
(4.52-12.68)

p-value1 <0.0001 <0.0001
Overall Survival (OS)
Months (median)

28.2 28.2 23.1 23.5

Hazard Ratio (HR)
(95%CI)

0.88
(0.66-1.17)

0.93
(0.72-1.22)

p-value1 0.3850 0.6137
1 p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logistic regression
2 CR=complete response; PR=partial response



15

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

Del19
GIOTRIF

(N=112)

Pemetrexed/
Cisplatin
(N=57)

GIOTRIF

(N=124)

Gemcitabine/
Cisplatin
(N=62)

Progression-free survival 
Months (median) 

13.8 5.6 13.1 5.6

Hazard Ratio (HR)
(95%CI)

0.26
(0.17-0.42)

0.20
(0.13-0.33)

p-value1 <0.0001 <0.0001
Overall Survival (OS)
Months (median)

33.3 21.1 31.4 18.4

Hazard Ratio (HR)
(95%CI)

0.54
(0.36-0.79)

0.64
(0.44-0.94)

p-value1 0.0015 0.0229

L858R
GIOTRIF

(N=91)

Pemetrexed/
Cisplatin
(N=47)

GIOTRIF

(N=92)

Gemcitabine/
Cisplatin
(N=46)

Progression-free survival 
Months (median) 

10.8 8.1 9.6 5.6

Hazard Ratio (HR)
(95%CI)

0.75
(0.48-1.19)

0.31
(0.19-0.52)

p-value1 0.2191 <0.0001
Overall Survival (OS)
Months (median)

27.6 40.3 19.6 24.3

Hazard Ratio (HR)
(95%CI)

1.30
(0.80-2.11)

1.22
(0.81-1.83)

p-value1 0.2919 0.3432
1 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 and 
chemotherapy, 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 to 
deterioration (see Table 8). Mean scores over time for overall quality of life, global health status and 
physical, role, cognitive, social and emotional functioning were significantly better for GIOTRIF.



16

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

LUX-Lung 3

Cough Dyspnoea Pain
% of patients improved a 67% vs. 60%; 

p=0.2133
65% vs. 50%; 

p=0.0078
60% vs. 48%; 

p=0.0427
Delay of median time to 
deterioration (months) a,b

27.0 vs. 8.0
HR 0.60; p=0.0062

10.4 vs. 2.9
HR 0.68; p=0.0129

4.2 vs. 3.1
HR 0.83; p=0.1882

LUX-Lung 6

Cough Dyspnoea Pain
% of patients improved a 76% vs. 55%; 

p=0.0003
71% vs. 48%; 

p<0.0001
65% vs. 47%; 

p=0.0017
Delay of median time to 
deterioration (months) a,b

31.1 vs. 10.3
HR 0.46; p=0.0001

7.7 vs. 1.7
HR 0.53; p<0.0001

6.9 vs. 3.4
HR 0.70; p=0.0220

a values presented for GIOTRIF vs. chemotherapy, p-value based on logistic regression
b 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 IV lung 
adenocarcinoma with EGFR mutations. Patients were enrolled in the first-line (N=61) or second-line setting 
(N=68) (i.e. after failure of 1 prior chemotherapy regimen). 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. Efficacy was similarly high in the group of patients who had received 
prior chemotherapy (N=68; ORR 57.4%; median PFS by independent review 8 months). The updated 
median OS for first- and second-line was 31.7 months and 23.6 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 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 include PFS by independent review and OS. Secondary endpoints include ORR 
and DCR. GIOTRIF significantly improved PFS and ORR in EGFR mutation positive patients compared to 
gefitinib. The efficacy results are summarized in Table 9.



17

Table 9: Efficacy results of GIOTRIF vs. gefitinib (LUX-Lung 7) based on primary analysis as of August 
2015.

GIOTRIF
(N=160)

Gefitinib
(N=159)

Hazard Ratio/
Odds Ratio

(95%CI)
p-value2

Median PFS (months), Overall 
Trial Population

18-months PFS rate
24-months PFS rate

11.0

27%
18%

10.9

15%
8%

HR 0.73
(0.57-0.95)

0.0165

Median OS (months)1, Overall 
Trial Population 

Alive at 18-months
Alive at 24-months

27.9

71%
61%

24.5

67%
51%

HR 0.86
(0.66, 1.12)

0.2580

Objective Response Rate 
(CR+PR)3

70% 56% OR 1.87
(1.12, 2.99)

0.0083
1OS 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, respectively
2p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on 
stratified logistic regression
3CR=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 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 patients with tumours harbouring either G719X (N=18), L861Q (N=16), or S768I substitution mutation 
(N=8), the confirmed ORR was 72.2%, 56.3%, 75.0%, respectively, and the median duration of response was 
13.2 months, 12.9 months and 26.3 months, respectively. 

In patients with tumours harbouring exon 20 insertions (N=23) the confirmed ORR was 8.7% and the median 
duration of response was 7.1 months. In patients with tumours harbouring de-novo T790M mutations (N=14) 
the confirmed ORR was 14.3% and the median duration of response was 8.3 months.

GIOTRIF in patients with NSCLC of squamous histology

The efficacy and safety of GIOTRIF as second-line treatment for patients with advanced NSCLC of 
squamous 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 were subsequently 
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 in tumour size and HRQOL.
Among 795 patients randomized, the majority were males (84%), white (73%), current or former smokers 
(95%) with baseline performance status ECOG 1 (67%) and ECOG 0 (33%).



18

Second-line GIOTRIF significantly improved PFS and OS of patients with squamous NSCLC compared to 
erlotinib. The efficacy results at the time of the primary analysis of OS including all randomized 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

(N=398)

Erlotinib 

(n=397)

Hazard Ratio/
Odds Ratio

(95%CI)

p-value2

PFS
Months (median) 2.63 1.94 HR 0.81

(0.69, 0.96)
0.0103

OS 
Months (median)

Alive at 12 months
Alive at 18 months

7.92

36.4%
22.0%

6.77

28.2%
14.4%

HR 0.81
(0.69, 0.95)

0.0077

Objective Response 
Rate (CR+PR)1

5.5% 2.8% OR 2.06
(0.98, 4.32)

0.0551

Duration of response 
Months (median)

7.29 3.71

1CR=complete response; PR=partial response
2p-value for PFS/OS based on stratified log-rank test; p-value for Objective Response Rate based on logistic regression

The overall survival hazard ratio in patients < 65 years of age was 0.68 (95% CI 0.55, 0.85) and in patients 
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 to 
deterioration (see Table 11). 



19

Table 11: Symptom outcomes for GIOTRIF vs. erlotinib in trial LUX-Lung 8 (EORTC QLQ-C30 & 
QLQ-LC13)

Cough Dyspnoea Pain
% of patients 
improveda, c

43% vs. 35%;
p=0.0294

51% vs. 44%; 
p=0.0605

40% vs. 39%; 
p=0.7752

Delay of time to 
deterioration 
(months)b, c

4.5 vs. 3.7
HR 0.89; p=0.2562

2.6 vs. 1.9
HR 0.79; p=0.0078

2.5 vs. 2.4
HR 0.99; p=0.8690

a values presented for GIOTRIF vs. erlotinib, p-value based on logistic regression
b p-value for time to deterioration based on stratified log-rank test
c p-values were not adjusted for multiplicity

Efficacy in EGFR-negative tumours has not been established.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of trials with this medicinal 
product in all subsets of the paediatric population in NSCLC indications (see section 4.2 for information on 
paediatric use).

5.2 Pharmacokinetic properties

Absorption
Following oral administration of GIOTRIF, Cmax of afatinib were observed approximately 2 to 5 hours post 
dose. Cmax and AUC0-∞ values increased slightly more than proportionally 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 to administration in the fasted state. Based on population 
pharmacokinetic data derived from clinical trials in various tumour types, an average decrease of 26% in 
AUCτ,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 sections 4.2 and 4.5).

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

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

Elimination
In humans, excretion of afatinib is primarily via the faeces. 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. Afatinib is eliminated with an effective half-life of
approximately 37 hours. Thus, steady state plasma concentrations of afatinib were achieved 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 terminal half-life of 344 h was estimated.

Special populations

Renal impairment
Less than 5% of a single dose of afatinib is excreted via the kidneys. Exposure to afatinib in subjects with 
renal impairment was compared to healthy volunteers following a single dose of 40 mg GIOTRIF. Subjects 
with moderate renal impairment (n=8; eGFR 30-59 mL/min/1.73m², according to the Modification of Diet in 
Renal Disease [MDRD] formula) had an exposure of 101% (Cmax) and 122% (AUC0-tz) in comparison to their 
healthy controls. Subjects with severe renal impairment (n=8; eGFR 15-29 mL/min/1.73m², according to the 



20

MDRD formula) had an exposure of 122% (Cmax) and 150% (AUC0-tz) in comparison to their healthy 
controls. Based on this trial and population pharmacokinetic analysis of data derived from clinical trials in 
various tumour types, it is concluded, that adjustments to the starting dose in patients with mild (eGFR 
60-89 mL/min/1.73m²), moderate (eGFR 30-59 mL/min/1.73m²), or severe (eGFR 15-29 mL/min/1.73m²) 
renal impairment are not necessary, but patients with severe impairment should be monitored (see 
“Population pharmacokinetic analysis in special populations” below and section 4.2). GIOTRIF has not been 
studied in patients with eGFR <15 mL/min/1.73m² 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 “Population pharmacokinetic analysis in special populations”
below). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment
(see section 4.2). The pharmacokinetics of afatinib have not been studied in subjects with severe 
(Child Pugh C) hepatic dysfunction (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 of the following 
covariates tested.

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

Body weight
Plasma exposure (AUCτ,ss) was increased by 26% for a 42 kg patient (2.5

th percentile) and decreased by 22% 
for a 95 kg patient (97.5th percentile) relative to a patient weighing 62 kg (median body weight of patients in 
the overall patient population). 

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

Race
Race had no effect on the pharmacokinetics of afatinib based on a population pharmacokinetic analysis, 
including patients of Asian, White, and Black racial groups. Data on Black racial groups was limited.

Renal impairment
Exposure to afatinib moderately increased with lowering of the creatinine clearance (CrCL, calculated 
according 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 a patient with CrCL 
of 90 mL/min 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. There was limited data available for moderate and severe 
hepatic impairment.

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 (limited data), or presence of liver metastases had no significant impact on the 
pharmacokinetics of afatinib. 



21

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 OATB1B1, 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 the metabolism 
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 an inhibitor or an inducer of CYP 
enzymes. Therefore, this medicinal product is unlikely to interact with other 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 are considered 
unlikely.

5.3 Preclinical safety data

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

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

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

A fertility study in male and female rats up to the maximum tolerated dose revealed no significant impact on 
fertility. The total systemic exposure (AUC0-24) in male and female rats was in the range or less than that 
observed in patients (1.3 times and 0.51 times, respectively).  
A study in rats up to the maximum tolerated doses revealed no significant impact on pre-/postnatal 
development. The highest total systemic exposure (AUC0-24) in female rats was less than that observed in 
patients (0.23 times).

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

Carcinogenicity
Carcinogenicity studies have not been conducted with GIOTRIF.



22

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core 

Lactose monohydrate 
Cellulose, microcrystalline (E460)
Silica, colloidal anhydrous (E551)
Crospovidone (type A)
Magnesium stearate (E470b) 

Film-coating 

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)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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



23

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 September 2013
Date of latest renewal: 16 May 2018

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu

http://www.ema.europa.eu


24

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETINGAUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



25

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
GERMANY

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports 

The requirements for submission of periodic safety update reports for this medicinal product are set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed 
RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the 
RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information being 

received that may lead to a significant change to the benefit/risk profile or as the result of an important 
(pharmacovigilance or risk minimisation) milestone being reached. 



26

ANNEX III

LABELLING AND PACKAGE LEAFLET



27

A. LABELLING



28

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (FOLDING BOX FOR BLISTER for 20 mg)

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 20 mg film-coated tablets
afatinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

7 x 1 film-coated tablets
14 x 1 film-coated tablets
28 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 
THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



29

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/13/879/001
EU/1/13/879/002 
EU/1/13/879/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

GIOTRIF 20 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



30

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

ALUMINIUM POUCH for 20 mg 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

GIOTRIF 20 mg film-coated tablets
afatinib

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

Do not open before use. 

Boehringer Ingelheim (logo)



31

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PERFORATED BLISTER for 20 mg 

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 20 mg tablets
afatinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not open before use.



32

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (FOLDING BOX FOR BLISTER for 30 mg)

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 30 mg film-coated tablets
afatinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

7 x 1 film-coated tablets
14 x 1 film-coated tablets
28 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 
THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



33

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/13/879/004
EU/1/13/879/005 
EU/1/13/879/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

GIOTRIF 30 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



34

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

ALUMINIUM POUCH for 30 mg 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

GIOTRIF 30 mg film-coated tablets
afatinib

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

Do not open before use. 

Boehringer Ingelheim (logo)



35

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PERFORATED BLISTER for 30 mg 

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 30 mg tablets
afatinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not open before use.



36

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (FOLDING BOX FOR BLISTER for 40 mg)

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 40 mg film-coated tablets
afatinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

7 x 1 film-coated tablets
14 x 1 film-coated tablets
28 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 
THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



37

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/13/879/007
EU/1/13/879/008 
EU/1/13/879/009

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

GIOTRIF 40 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



38

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

ALUMINIUM POUCH for 40 mg 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

GIOTRIF 40 mg film-coated tablets
afatinib

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

Do not open before use. 

Boehringer Ingelheim (logo)



39

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PERFORATED BLISTER for 40 mg 

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 40 mg tablets
afatinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not open before use.



40

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (FOLDING BOX FOR BLISTER for 50 mg)

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 50 mg film-coated tablets
afatinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

7 x 1 film-coated tablets
14 x 1 film-coated tablets
28 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 
THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



41

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/13/879/010
EU/1/13/879/011 
EU/1/13/879/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

GIOTRIF 50 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



42

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

ALUMINIUM POUCH for 50 mg 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

GIOTRIF 50 mg film-coated tablets
afatinib

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

Do not open before use. 

Boehringer Ingelheim (logo)



43

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PERFORATED BLISTER for 50 mg 

1. NAME OF THE MEDICINAL PRODUCT

GIOTRIF 50 mg tablets
afatinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not open before use.



44

B. PACKAGE LEAFLET



45

Package leaflet: Information for the patient

GIOTRIF 20 mg film-coated tablets
afatinib

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

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.
- If any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please 

tell your doctor or pharmacist. See section 4.

What is in this leaflet

1. What GIOTRIF is and what it is used for 
2. What you need to know before you take GIOTRIF 
3. How to take GIOTRIF 
4. Possible side effects 
5. How to store GIOTRIF 
6. Contents of the pack and other information

1. What GIOTRIF is and what it is used for

GIOTRIF is a medicine which contains the active substance afatinib. It works by blocking the activity of a 
group of proteins called the ErbB family (including EGFR [epidermal growth factor receptor or ErbB1], 
HER2 [ErbB2], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells, and 
can be affected by changes (mutations) in the genes that produce them. By blocking the activity of these
proteins this medicine can inhibit growth and spread of cancer cells.

This medicine is used on its own to treat adult patients with a specific type of cancer of the lung (non-small 
cell lung cancer):

 that is identified by a change (mutation) in the gene for EGFR. GIOTRIF can be prescribed to you as 
your first treatment or if prior chemotherapy treatment has been insufficient.

 of squamous type if prior chemotherapy treatment has been insufficient. 

2. What you need to know before you take GIOTRIF

Do not take GIOTRIF
- if you are allergic to afatinib or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions 
Talk to your doctor or pharmacist before taking this medicine:

 if you are female, have a low body weight of less than 50 kg or have kidney problems. If any of 
these apply to you, your doctor may monitor you more closely as the side effects may be more 
pronounced.

 if you have a history of lung inflammation (interstitial lung disease).
 if you have liver problems. Your doctor may do some liver tests. Treatment with this medicine is not 

recommended if you have a severe liver disease.
 if you have a history of eye problems such as severe dry eyes, inflammation of the transparent layer 

at the front of the eye (cornea) or ulcers involving the outer part of the eye, or if you use contact 
lenses.



46

 if you have a history of heart problems. Your doctor may want to monitor you more closely.

Inform your doctor immediately while taking this medicine:
 if you develop diarrhoea. Treatment at the first signs of diarrhoea is important.
 if you develop skin rash. Early treatment of skin rash is important.
 if you develop new or sudden worsening of shortness of breath, possibly with a cough or fever. 

These could be symptoms of an inflammation of the lungs (interstitial lung disease) and can be life-
threatening.

    if you have severe pain in your stomach or intestines, fever, chills, sickness, vomiting, or abdominal 
rigidity or bloating, as these could be symptoms of a tear in the wall of your stomach or intestines 
(‘gastrointestinal perforation’). Also, tell your doctor if you had gastrointestinal ulcers or diverticular 
disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to 
treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase 
this risk.

 if you develop acute or worsening redness and pain in the eye, increased eye watering, blurred vision 
and/or sensitivity to light. You may need urgent treatment.

See also section 4 “Possible side effects”.

Children and adolescents
GIOTRIF has not been studied in children or adolescents.  Do not give this medicine to children or 
adolescents under the age of 18 years. 

Other medicines and GIOTRIF
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, 
including herbal medicines and medicines obtained without a prescription.

In particular, if taken before GIOTRIF, the following medicines may increase the blood levels of GIOTRIF 
and therefore the risk of side effects. They should therefore be taken as far apart in time as possible from 
GIOTRIF. This means preferably 6 hours (for medicines taken twice daily) or 12 hours (for medicines taken
once daily) apart from GIOTRIF:

 Ritonavir, ketoconazole (except in shampoo), itraconazole, erythromycin, nelfinavir,
saquinavir - used to treat different kinds of infections. 

 Verapamil, quinidine, amiodarone - used to treat heart conditions. 
 Cyclosporine A, tacrolimus - medicines that affect your immune system. 

The following medicines may reduce the effectiveness of GIOTRIF:
 Carbamazepine, phenytoin, phenobarbital - used to treat seizures.
 St. John’s wort (Hypericum perforatum), a herbal medicine to treat depression.
 Rifampicin, an antibiotic used to treat tuberculosis.

Ask your doctor if you are unsure of when to take these medicines.

GIOTRIF may increase the blood levels of other medicines including but not limited to:
 Sulfasalazine, used to treat inflammation/infection.
 Rosuvastatin, used for lowering cholesterol.

Tell your doctor before taking these medicines together with GIOTRIF.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Pregnancy
You should avoid becoming pregnant while taking this medicine. If you could become pregnant, you should 
use adequate birth control methods during treatment and for at least 1 month after taking the last dose of this 
medicine. This is because there may be a risk that an unborn baby is harmed.



47

If you become pregnant while receiving this medicine, you should immediately inform your doctor. Your 
doctor will decide with you whether treatment should be continued or not.

If you plan to become pregnant after taking the last dose of this medicine, you should ask your doctor for 
advice as your body may not have fully eliminated this medicine. 

Breast-feeding
Do not breast-feed while taking this medicine as a risk to the breast-fed child cannot be excluded.

Driving and using machines
If you experience treatment-related symptoms affecting your eye sight (e.g. redness and/or irritation of the 
eye, dry eye, tearing, light-sensitivity) or your ability to concentrate and react, it is recommended that you do 
not drive or use machines until the side effect disappears (see section 4 Possible side effects).

GIOTRIF contains lactose
This medicine contains a sugar called lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take GIOTRIF

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure.

Dosage
The recommended dose is 40 mg each day.

Your doctor may adjust (increase or decrease) your dose depending on how well you tolerate this medicine. 

When to take GIOTRIF
 It is important to take this medicine without food
 Take this medicine at least 1 hour before eating, or
 If you have already eaten, wait at least 3 hours before taking this medicine.
 Take this medicine once daily about the same time each day. This makes it easier to remember to 

take this medicine.
 Do not break, chew or crush the tablet.
 Swallow the tablet whole with a glass of still water.

GIOTRIF is to be taken by mouth. If you have difficulties swallowing the tablet, dissolve it in a glass of still 
water. No other liquids should be used. Drop the tablet into the water without crushing it, and occasionally 
stir for up to 15 min until the tablet is broken up into very small particles. Drink the liquid straight away. 
Then fill the glass again with water and drink it to make sure all medicine is taken. 

If you are not able to swallow and have a gastric tube your doctor might suggest that the medicine is given to 
you via the tube.

If you take more GIOTRIF than you should
Contact your doctor or pharmacist immediately. You may experience increased side effects and your doctor 
may interrupt your treatment and provide supportive care.

If you forget to take GIOTRIF
 If your next scheduled dose is more than 8 hours away, take the missed dose as soon as you 

remember. 
 If your next scheduled dose is due within 8 hours, skip the missed dose and take your next dose at 

the usual time. Then carry on taking your tablets at regular times as usual. 
Do not take a double dose (two tablets instead of one at the same time) to make up for a missed dose.



48

If you stop taking GIOTRIF
Do not stop taking this medicine without first consulting your doctor. It is important to take this medicine 
every day, as long as your doctor prescribes it for you. If you do not take this medicine as prescribed by your 
doctor your cancer may grow again.

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

4. Possible side effects

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

Contact your doctor as soon as possible if you suffer from any of the serious side effects listed below. In 
some cases your doctor may need to interrupt treatment and reduce your dose or stop treatment:

 Diarrhoea (very common, may affect more than 1 in 10 people). 
Diarrhoea lasting more than 2 days or more severe diarrhoea may lead to fluid loss (common, may 
affect up to 1 in 10 people), low blood potassium (common) and worsening kidney function 
(common). Diarrhoea can be treated. At the first signs of diarrhoea drink plenty of fluids. Contact 
your doctor immediately and start appropriate antidiarrhoeal treatment as soon as possible. You 
should have antidiarrhoeal medicine available prior to taking GIOTRIF. 

 Skin rash (very common).
It is important to treat the rash early. Tell your doctor if a rash starts.  If treatment for rash is not 
working and the rash is getting more severe (for example, you have peeling or blistering of the skin)
you should notify your doctor immediately, since your doctor may decide to stop your treatment 
with GIOTRIF.  Rash may occur or worsen in areas exposed to sun. Sun protection with protective 
clothing and sunscreen is recommended.

 Inflammation of the lungs (uncommon, may affect up to 1 in 100 people) called “interstitial lung 
disease”. 
Tell your doctor immediately if you develop new or sudden worsening of shortness of breath, 
possibly with a cough or fever.

 Eye irritation or inflammation
Eye irritation or inflammation may occur (conjunctivitis/keratoconjunctivitis occurs commonly and 
keratitis uncommonly). Tell your doctor if you have sudden or worsening of eye symptoms such as 
pain or redness or dry eye.

If you experience any of the symptoms above, contact your doctor as soon as possible.

The following other side effects have also been reported:

Very common side effects (may affect more than 1 in 10 people):
 Mouth sores and inflammation
 Nail infection
 Decreased appetite
 Bleeding from the nose
 Nausea
 Vomiting
 Itching
 Dry skin

Common side effects (may affect up to 1 in 10 people):
 Pain, redness, swelling or peeling of the skin of your hands and feet



49

 Increased levels of the liver enzymes (aspartate aminotransferase and alanine aminotransferase) in 
blood tests.

 Inflammation of the lining of the bladder with burning sensations during urination and frequent, 
urgent need to urinate (cystitis)

 Abnormal taste sensations (dysgeusia)
 Stomach pain, indigestion, heartburn
 Lip inflammation
 Decreased weight
 Runny nose 
 Muscle spasms
 Fever
 Nail problems

Uncommon side effects (may affect up to 1 in 100 people):
 Inflammation of the pancreas (pancreatitis)
 Occurrence of a tear in the wall of your stomach or intestines (gastrointestinal perforation)

Rare side effects (may affect up to 1 in 1,000 people):
 Severe blistering or peeling of skin (suggestive of Stevens-Johnson syndrome and toxic epidermal 

necrolysis)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 
in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store GIOTRIF

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

Do not use this medicine after the expiry date which is stated on the carton, the pouch and the blister after 
EXP. The expiry date refers to the last day of that month.

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

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What GIOTRIF contains 
- The active substance is afatinib. Each film-coated tablet contains 20 mg of afatinib (as dimaleate).
- The other ingredients are lactose monohydrate, microcrystalline cellulose (E460), colloidal anhydrous 

silica (E551), crospovidone type A, magnesium stearate (E470b), hypromellose (E464), macrogol 400, 
titanium dioxide (E171), talc (E553b), polysorbate 80 (E433). 

What GIOTRIF looks like and contents of the pack
GIOTRIF 20 mg film-coated tablets are white to yellowish and round shaped. They are debossed with the 
code “T20” on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF film-coated tablets are available in packs containing 1, 2 or 4 perforated unit dose blisters. Each 
blister contains 7 x 1 film-coated tablets and is packed in an aluminium pouch together with a desiccant 
sachet that should not be swallowed.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


50

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



51

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti Filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211



52

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in {MM/YYYY}

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu


53

Package leaflet: Information for the patient

GIOTRIF 30 mg film-coated tablets
afatinib

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

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.
- If any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please 

tell your doctor or pharmacist. See section 4.

What is in this leaflet

1. What GIOTRIF is and what it is used for
2. What you need to know before you take GIOTRIF 
3. How to take GIOTRIF 
4. Possible side effects 
5. How to store GIOTRIF 
6. Contents of the pack and other information

1. What GIOTRIF is and what it is used for

GIOTRIF is a medicine which contains the active substance afatinib. It works by blocking the activity of a 
group of proteins called the ErbB family (including EGFR [epidermal growth factor receptor or ErbB1], 
HER2 [ErbB2], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells, and 
can be affected by changes (mutations) in the genes that produce them. By blocking the activity of these 
proteins this medicine can inhibit growth and spread of cancer cells.

This medicine is used on its own to treat adult patients with a specific type of cancer of the lung (non-small 
cell lung cancer):

 that is identified by a change (mutation) in the gene for EGFR. GIOTRIF can be prescribed to you as 
your first treatment or if prior chemotherapy treatment has been insufficient.

 of squamous type if prior chemotherapy treatment has been insufficient. 

2. What you need to know before you take GIOTRIF

Do not take GIOTRIF
- if you are allergic to afatinib or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions 
Talk to your doctor or pharmacist before taking this medicine:

 if you are female, have a low body weight of less than 50 kg or have kidney problems. If any of 
these apply to you, your doctor may monitor you more closely as the side effects may be more 
pronounced.

 if you have a history of lung inflammation (interstitial lung disease).
 if you have liver problems. Your doctor may do some liver tests. Treatment with this medicine is not 

recommended if you have a severe liver disease.
 if you have a history of eye problems such as severe dry eyes, inflammation of the transparent layer 

at the front of the eye (cornea) or ulcers involving the outer part of the eye, or if you use contact 
lenses.



54

 if you have a history of heart problems. Your doctor may want to monitor you more closely.

Inform your doctor immediately while taking this medicine:
 if you develop diarrhoea. Treatment at the first signs of diarrhoea is important.
 if you develop skin rash. Early treatment of skin rash is important. 
 if you develop new or sudden worsening of shortness of breath, possibly with a cough or fever. 

These could be symptoms of an inflammation of the lungs (interstitial lung disease) and can be life-
threatening.

 if you have severe pain in your stomach or intestines, fever, chills, sickness, vomiting, or abdominal 
rigidity or bloating, as these could be symptoms of a tear in the wall of your stomach or intestines 
(‘gastrointestinal perforation’). Also, tell your doctor if you had gastrointestinal ulcers or diverticular
disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to 
treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase 
this risk.

 if you develop acute or worsening redness and pain in the eye, increased eye watering, blurred vision 
and/or sensitivity to light. You may need urgent treatment.

See also section 4 “Possible side effects”.

Children and adolescents
GIOTRIF has not been studied in children or adolescents.  Do not give this medicine to children or 
adolescents under the age of 18 years. 

Other medicines and GIOTRIF
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, 
including herbal medicines and medicines obtained without a prescription.

In particular, if taken before GIOTRIF, the following medicines may increase the blood levels of GIOTRIF 
and therefore the risk of side effects. They should therefore be taken as far apart in time as possible from 
GIOTRIF. This means preferably 6 hours (for medicines taken twice daily) or 12 hours (for medicines taken 
once daily) apart from GIOTRIF:

 Ritonavir, ketoconazole (except in shampoo), itraconazole, erythromycin, nelfinavir, 
saquinavir - used to treat different kinds of infections. 

 Verapamil, quinidine, amiodarone - used to treat heart conditions. 
 Cyclosporine A, tacrolimus - medicines that affect your immune system. 

The following medicines may reduce the effectiveness of GIOTRIF:
 Carbamazepine, phenytoin, phenobarbital - used to treat seizures.
 St. John’s wort (Hypericum perforatum), a herbal medicine to treat depression.
 Rifampicin, an antibiotic used to treat tuberculosis.

Ask your doctor if you are unsure of when to take these medicines.

GIOTRIF may increase the blood levels of other medicines including but not limited to:
 Sulfasalazine, used to treat inflammation/infection.
 Rosuvastatin, used for lowering cholesterol.

Tell your doctor before taking these medicines together with GIOTRIF.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Pregnancy
You should avoid becoming pregnant while taking this medicine. If you could become pregnant, you should 
use adequate birth control methods during treatment and for at least 1 month after taking the last dose of this 
medicine. This is because there may be a risk that an unborn baby is harmed.



55

If you become pregnant while receiving this medicine, you should immediately inform your doctor. Your 
doctor will decide with you whether treatment should be continued or not.

If you plan to become pregnant after taking the last dose of this medicine, you should ask your doctor for 
advice as your body may not have fully eliminated this medicine. 

Breast-feeding
Do not breast-feed while taking this medicine as a risk to the breast-fed child cannot be excluded.

Driving and using machines
If you experience treatment-related symptoms affecting your eye sight (e.g. redness and/or irritation of the 
eye, dry eye, tearing, light-sensitivity) or your ability to concentrate and react, it is recommended that you do 
not drive or use machines until the side effect disappears (see section 4 Possible side effects).

GIOTRIF contains lactose
This medicine contains a sugar called lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take GIOTRIF

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure.

Dosage
The recommended dose is 40 mg each day. 

Your doctor may adjust (increase or decrease) your dose depending on how well you tolerate this medicine. 

When to take GIOTRIF
 It is important to take this medicine without food
 Take this medicine at least 1 hour before eating, or
 If you have already eaten, wait at least 3 hours before taking this medicine.
 Take this medicine once daily about the same time each day. This makes it easier to remember to 

take this medicine.
 Do not break, chew or crush the tablet.
 Swallow the tablet whole with a glass of still water.

GIOTRIF is to be taken by mouth. If you have difficulties swallowing the tablet, dissolve it in a glass of still 
water. No other liquids should be used. Drop the tablet into the water without crushing it, and occasionally 
stir for up to 15 min until the tablet is broken up into very small particles. Drink the liquid straight away. 
Then fill the glass again with water and drink it to make sure all medicine is taken. 

If you are not able to swallow and have a gastric tube your doctor might suggest that the medicine is given to 
you via the tube.

If you take more GIOTRIF than you should
Contact your doctor or pharmacist immediately. You may experience increased side effects and your doctor 
may interrupt your treatment and provide supportive care.

If you forget to take GIOTRIF
 If your next scheduled dose is more than 8 hours away, take the missed dose as soon as you 

remember. 
 If your next scheduled dose is due within 8 hours, skip the missed dose and take your next dose at 

the usual time. Then carry on taking your tablets at regular times as usual. 
Do not take a double dose (two tablets instead of one at the same time) to make up for a missed dose.



56

If you stop taking GIOTRIF
Do not stop taking this medicine without first consulting your doctor. It is important to take this medicine 
every day, as long as your doctor prescribes it for you. If you do not take this medicine as prescribed by your 
doctor your cancer may grow again.

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

4. Possible side effects

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

Contact your doctor as soon as possible if you suffer from any of the serious side effects listed below. In 
some cases your doctor may need to interrupt treatment and reduce your dose or stop treatment:

 Diarrhoea (very common, may affect more than 1 in 10 people). 
Diarrhoea lasting more than 2 days or more severe diarrhoea may lead to fluid loss (common, may 
affect up to 1 in 10 people), low blood potassium (common) and worsening kidney function 
(common). Diarrhoea can be treated. At the first signs of diarrhoea drink plenty of fluids. Contact 
your doctor immediately and start appropriate antidiarrhoeal treatment as soon as possible. You 
should have antidiarrhoeal medicine available prior to taking GIOTRIF. 

 Skin rash (very common).
It is important to treat the rash early. Tell your doctor if a rash starts.  If treatment for rash is not 
working and the rash is getting more severe (for example, you have peeling or blistering of the skin)
you should notify your doctor immediately, since your doctor may decide to stop your treatment 
with GIOTRIF.  Rash may occur or worsen in areas exposed to sun. Sun protection with protective 
clothing and sunscreen is recommended.

 Inflammation of the lungs (uncommon, may affect up to 1 in 100 people) called “interstitial lung 
disease”. 
Tell your doctor immediately if you develop new or sudden worsening of shortness of breath, 
possibly with a cough or fever. 

 Eye irritation or inflammation
Eye irritation or inflammation may occur (conjunctivitis/keratoconjunctivitis occurs commonly and 
keratitis uncommonly). Tell your doctor if you have sudden or worsening of eye symptoms such as 
pain or redness or dry eye.

If you experience any of the symptoms above, contact your doctor as soon as possible.

The following other side effects have also been reported:

Very common side effects (may affect more than 1 in 10 people):
 Mouth sores and inflammation
 Nail infection
 Decreased appetite
 Bleeding from the nose
 Nausea
 Vomiting
 Itching
 Dry skin

Common side effects (may affect up to 1 in 10 people):
 Pain, redness, swelling or peeling of the skin of your hands and feet



57

 Increased levels of the liver enzymes (aspartate aminotransferase and alanine aminotransferase) in 
blood tests.

 Inflammation of the lining of the bladder with burning sensations during urination and frequent, 
urgent need to urinate (cystitis)

 Abnormal taste sensations (dysgeusia)
 Stomach pain, indigestion, heartburn
 Lip inflammation
 Decreased weight
 Runny nose 
 Muscle spasms
 Fever
 Nail problems

Uncommon side effects (may affect up to 1 in 100 people):
 Inflammation of the pancreas (pancreatitis)
    Occurrence of a tear in the wall of your stomach or intestines (gastrointestinal perforation)

Rare side effects (may affect up to 1 in 1,000 people):
 Severe blistering or peeling of skin (suggestive of Stevens-Johnson syndrome and toxic epidermal 

necrolysis)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 
in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store GIOTRIF

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

Do not use this medicine after the expiry date which is stated on the carton, the pouch and the blister after 
EXP. The expiry date refers to the last day of that month.

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

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What GIOTRIF contains 
- The active substance is afatinib. Each film-coated tablet contains 30 mg of afatinib (as dimaleate).
- The other ingredients are lactose monohydrate, microcrystalline cellulose (E460), colloidal anhydrous 

silica (E551), crospovidone type A, magnesium stearate (E470b), hypromellose  (E464), 
macrogol 400, titanium dioxide (E171), talc (E553b), polysorbate 80 (E433), indigo carmine (E132) 
aluminium lake. 

What GIOTRIF looks like and contents of the pack
GIOTRIF 30 mg film-coated tablets are dark blue and round shaped. They are debossed with the code “T30” 
on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF film-coated tablets are available in packs containing 1, 2 or 4 perforated unit dose blisters. Each 
blister contains 7 x 1 film-coated tablets and is packed in an aluminium pouch together with a desiccant 
sachet that should not be swallowed.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


58

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



59

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti Filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211



60

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in {MM/YYYY}

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu


61

Package leaflet: Information for the patient

GIOTRIF 40 mg film-coated tablets
afatinib

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

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.
- If any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please 

tell your doctor or pharmacist. See section 4.

What is in this leaflet

1. What GIOTRIF is and what it is used for 
2. What you need to know before you take GIOTRIF 
3. How to take GIOTRIF 
4. Possible side effects 
5. How to store GIOTRIF 
6. Contents of the pack and other information

1. What GIOTRIF is and what it is used for

GIOTRIF is a medicine which contains the active substance afatinib. It works by blocking the activity of a 
group of proteins called the ErbB family (including EGFR [epidermal growth factor receptor or ErbB1], 
HER2 [ErbB2], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells, and 
can be affected by changes (mutations) in the genes that produce them. By blocking the activity of these 
proteins this medicine can inhibit growth and spread of cancer cells.

This medicine is used on its own to treat adult patients with a specific type of cancer of the lung (non-small 
cell lung cancer):

 that is identified by a change (mutation) in the gene for EGFR. GIOTRIF can be prescribed to you as 
your first treatment or if prior chemotherapy treatment has been insufficient.

 of squamous type if prior chemotherapy treatment has been insufficient. 

2. What you need to know before you take GIOTRIF

Do not take GIOTRIF
- if you are allergic to afatinib or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions 
Talk to your doctor or pharmacist before taking this medicine:

 if you are female, have a low body weight of less than 50 kg or have kidney problems. If any of 
these apply to you, your doctor may monitor you more closely as the side effects may be more 
pronounced.

 if you have a history of lung inflammation (interstitial lung disease).
 if you have liver problems. Your doctor may do some liver tests. Treatment with this medicine is not 

recommended if you have a severe liver disease.
 if you have a history of eye problems such as severe dry eyes, inflammation of the transparent layer 

at the front of the eye (cornea) or ulcers involving the outer part of the eye, or if you use contact 
lenses.



62

 if you have a history of heart problems. Your doctor may want to monitor you more closely.

Inform your doctor immediately while taking this medicine:
 if you develop diarrhoea. Treatment at the first signs of diarrhoea is important.
 if you develop skin rash. Early treatment of skin rash is important. 
 if you develop new or sudden worsening of shortness of breath, possibly with a cough or fever. 

These could be symptoms of an inflammation of the lungs (interstitial lung disease) and can be life-
threatening.

 if you have severe pain in your stomach or intestines, fever, chills, sickness, vomiting, or abdominal 
rigidity or bloating, as these could be symptoms of a tear in the wall of your stomach or intestines 
(‘gastrointestinal perforation’). Also, tell your doctor if you had gastrointestinal ulcers or diverticular 
disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to 
treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase 
this risk.

 if you develop acute or worsening redness and pain in the eye, increased eye watering, blurred vision 
and/or sensitivity to light. You may need urgent treatment.

See also section 4 “Possible side effects”.

Children and adolescents
GIOTRIF has not been studied in children or adolescents.  Do not give this medicine to children or 
adolescents under the age of 18 years. 

Other medicines and GIOTRIF
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, 
including herbal medicines and medicines obtained without a prescription.

In particular, if taken before GIOTRIF, the following medicines may increase the blood levels of GIOTRIF 
and therefore the risk of side effects. They should therefore be taken as far apart in time as possible from 
GIOTRIF. This means preferably 6 hours (for medicines taken twice daily) or 12 hours (for medicines taken 
once daily) apart from GIOTRIF:

 Ritonavir, ketoconazole (except in shampoo), itraconazole, erythromycin, nelfinavir, 
saquinavir - used to treat different kinds of infections. 

 Verapamil, quinidine, amiodarone - used to treat heart conditions. 
 Cyclosporine A, tacrolimus - medicines that affect your immune system. 

The following medicines may reduce the effectiveness of GIOTRIF:
 Carbamazepine, phenytoin, phenobarbital - used to treat seizures.
 St. John’s wort (Hypericum perforatum), a herbal medicine to treat depression.
 Rifampicin, an antibiotic used to treat tuberculosis.

Ask your doctor if you are unsure of when to take these medicines.

GIOTRIF may increase the blood levels of other medicines including but not limited to:
 Sulfasalazine, used to treat inflammation/infection.
 Rosuvastatin, used for lowering cholesterol.

Tell your doctor before taking these medicines together with GIOTRIF.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Pregnancy
You should avoid becoming pregnant while taking this medicine. If you could become pregnant, you should 
use adequate birth control methods during treatment and for at least 1 month after taking the last dose of this 
medicine. This is because there may be a risk that an unborn baby is harmed.



63

If you become pregnant while receiving this medicine, you should immediately inform your doctor. Your 
doctor will decide with you whether treatment should be continued or not.

If you plan to become pregnant after taking the last dose of this medicine, you should ask your doctor for 
advice as your body may not have fully eliminated this medicine. 

Breast-feeding
Do not breast-feed while taking this medicine as a risk to the breast-fed child cannot be excluded.

Driving and using machines
If you experience treatment-related symptoms affecting your eye sight (e.g. redness and/or irritation of the 
eye, dry eye, tearing, light-sensitivity) or your ability to concentrate and react, it is recommended that you do 
not drive or use machines until the side effect disappears (see section 4 Possible side effects).

GIOTRIF contains lactose
This medicine contains a sugar called lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take GIOTRIF

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure.

Dosage
The recommended dose is 40 mg each day. 

Your doctor may adjust (increase or decrease) your dose depending on how well you tolerate this medicine. 

When to take GIOTRIF
 It is important to take this medicine without food
 Take this medicine at least 1 hour before eating, or
 If you have already eaten, wait at least 3 hours before taking this medicine.
 Take this medicine once daily about the same time each day. This makes it easier to remember to 

take this medicine.
 Do not break, chew or crush the tablet.
 Swallow the tablet whole with a glass of still water.

GIOTRIF is to be taken by mouth. If you have difficulties swallowing the tablet, dissolve it in a glass of still 
water. No other liquids should be used. Drop the tablet into the water without crushing it, and occasionally 
stir for up to 15 min until the tablet is broken up into very small particles. Drink the liquid straight away. 
Then fill the glass again with water and drink it to make sure all medicine is taken. 

If you are not able to swallow and have a gastric tube your doctor might suggest that the medicine is given to 
you via the tube.

If you take more GIOTRIF than you should
Contact your doctor or pharmacist immediately. You may experience increased side effects and your doctor 
may interrupt your treatment and provide supportive care.

If you forget to take GIOTRIF
 If your next scheduled dose is more than 8 hours away, take the missed dose as soon as you 

remember. 
 If your next scheduled dose is due within 8 hours, skip the missed dose and take your next dose at 

the usual time. Then carry on taking your tablets at regular times as usual. 
Do not take a double dose (two tablets instead of one at the same time) to make up for a missed dose.



64

If you stop taking GIOTRIF
Do not stop taking this medicine without first consulting your doctor. It is important to take this medicine 
every day, as long as your doctor prescribes it for you. If you do not take this medicine as prescribed by your 
doctor your cancer may grow again.

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

4. Possible side effects

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

Contact your doctor as soon as possible if you suffer from any of the serious side effects listed below. In 
some cases your doctor may need to interrupt treatment and reduce your dose or stop treatment:

 Diarrhoea (very common, may affect more than 1 in 10 people). 
Diarrhoea lasting more than 2 days or more severe diarrhoea may lead to fluid loss (common, may 
affect up to 1 in 10 people), low blood potassium (common) and worsening kidney function 
(common). Diarrhoea can be treated. At the first signs of diarrhoea drink plenty of fluids. Contact 
your doctor immediately and start appropriate antidiarrhoeal treatment as soon as possible. You 
should have antidiarrhoeal medicine available prior to taking GIOTRIF. 

 Skin rash (very common).
It is important to treat the rash early. Tell your doctor if a rash starts.  If treatment for rash is not 
working and the rash is getting more severe (for example, you have peeling or blistering of the skin)
you should notify your doctor immediately, since your doctor may decide to stop your treatment 
with GIOTRIF.  Rash may occur or worsen in areas exposed to sun. Sun protection with protective 
clothing and sunscreen is recommended.

 Inflammation of the lungs (uncommon, may affect up to 1 in 100 people) called “interstitial lung 
disease”. 
Tell your doctor immediately if you develop new or sudden worsening of shortness of breath, 
possibly with a cough or fever. 

 Eye irritation or inflammation
Eye irritation or inflammation may occur (conjunctivitis/keratoconjunctivitis occurs commonly and 
keratitis uncommonly). Tell your doctor if you have sudden or worsening of eye symptoms such as 
pain or redness or dry eye.

If you experience any of the symptoms above, contact your doctor as soon as possible.

The following other side effects have also been reported:

Very common side effects (may affect more than 1 in 10 people):
 Mouth sores and inflammation
 Nail infection
 Decreased appetite
 Bleeding from the nose
 Nausea
 Vomiting
 Itching
 Dry skin

Common side effects (may affect up to 1 in 10 people):
 Pain, redness, swelling or peeling of the skin of your hands and feet



65

 Increased levels of the liver enzymes (aspartate aminotransferase and alanine aminotransferase) in 
blood tests.

 Inflammation of the lining of the bladder with burning sensations during urination and frequent, 
urgent need to urinate (cystitis)

 Abnormal taste sensations (dysgeusia)
 Stomach pain, indigestion, heartburn
 Lip inflammation
 Decreased weight
 Runny nose 
 Muscle spasms
 Fever
 Nail problems

Uncommon side effects (may affect up to 1 in 100 people):
 Inflammation of the pancreas (pancreatitis)
 Occurrence of a tear in the wall of your stomach or intestines (gastrointestinal perforation)

Rare side effects (may affect up to 1 in 1,000 people):
 Severe blistering or peeling of skin (suggestive of Stevens-Johnson syndrome and toxic epidermal 

necrolysis)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 
in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store GIOTRIF

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

Do not use this medicine after the expiry date which is stated on the carton, the pouch and the blister after 
EXP. The expiry date refers to the last day of that month.

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

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What GIOTRIF contains 
- The active substance is afatinib. Each film-coated tablet contains 40 mg of afatinib (as dimaleate).
- The other ingredients are lactose monohydrate, microcrystalline cellulose (E460), colloidal anhydrous 

silica (E551), crospovidone type A, magnesium stearate (E470b), hypromellose  (E464), 
macrogol 400, titanium dioxide (E171), talc (E553b), polysorbate 80 (E433), indigo carmine (E132) 
aluminium lake. 

What GIOTRIF looks like and contents of the pack
GIOTRIF 40 mg film-coated tablets are light blue and round shaped. They are debossed with the code “T40” 
on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF film-coated tablets are available in packs containing 1, 2 or 4 perforated unit dose blisters. Each 
blister contains 7 x 1 film-coated tablets and is packed in an aluminium pouch together with a desiccant 
sachet that should not be swallowed.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


66

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



67

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti Filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211



68

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in {MM/YYYY}

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu


69

Package leaflet: Information for the patient

GIOTRIF 50 mg film-coated tablets
afatinib

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

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.
- If any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please 

tell your doctor or pharmacist. See section 4.

What is in this leaflet

1. What GIOTRIF is and what it is used for 
2. What you need to know before you take GIOTRIF 
3. How to take GIOTRIF 
4. Possible side effects 
5. How to store GIOTRIF 
6. Contents of the pack and other information

1. What GIOTRIF is and what it is used for

GIOTRIF is a medicine which contains the active substance afatinib. It works by blocking the activity of a 
group of proteins called the ErbB family (including EGFR [epidermal growth factor receptor or ErbB1], 
HER2 [ErbB2], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells, and 
can be affected by changes (mutations) in the genes that produce them. By blocking the activity of these 
proteins this medicine can inhibit growth and spread of cancer cells.

This medicine is used on its own to treat adult patients with a specific type of cancer of the lung (non-small 
cell lung cancer):

 that is identified by a change (mutation) in the gene for EGFR. GIOTRIF can be prescribed to you as 
your first treatment or if prior chemotherapy treatment has been insufficient.

 of squamous type if prior chemotherapy treatment has been insufficient. 

2. What you need to know before you take GIOTRIF

Do not take GIOTRIF
- if you are allergic to afatinib or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions 
Talk to your doctor or pharmacist before taking this medicine:

 if you are female, have a low body weight of less than 50 kg or have kidney problems. If any of 
these apply to you, your doctor may monitor you more closely as the side effects may be more 
pronounced.

 if you have a history of lung inflammation (interstitial lung disease).
 if you have liver problems. Your doctor may do some liver tests. Treatment with this medicine is not 

recommended if you have a severe liver disease.
 if you have a history of eye problems such as severe dry eyes, inflammation of the transparent layer 

at the front of the eye (cornea) or ulcers involving the outer part of the eye, or if you use contact 
lenses.



70

 if you have a history of heart problems. Your doctor may want to monitor you more closely.

Inform your doctor immediately while taking this medicine:
 if you develop diarrhoea. Treatment at the first signs of diarrhoea is important.
 if you develop skin rash. Early treatment of skin rash is important. 
 if you develop new or sudden worsening of shortness of breath, possibly with a cough or fever. 

These could be symptoms of an inflammation of the lungs (interstitial lung disease) and can be life-
threatening.

 if you have severe pain in your stomach or intestines, fever, chills, sickness, vomiting, or abdominal 
rigidity or bloating, as these could be symptoms of a tear in the wall of your stomach or intestines 
(‘gastrointestinal perforation’). Also, tell your doctor if you had gastrointestinal ulcers or diverticular 
disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to 
treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase 
this risk.

 if you develop acute or worsening redness and pain in the eye, increased eye watering, blurred vision 
and/or sensitivity to light. You may need urgent treatment.

See also section 4 “Possible side effects”.

Children and adolescents
GIOTRIF has not been studied in children or adolescents.  Do not give this medicine to children or 
adolescents under the age of 18 years. 

Other medicines and GIOTRIF
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, 
including herbal medicines and medicines obtained without a prescription.

In particular, if taken before GIOTRIF, the following medicines may increase the blood levels of GIOTRIF 
and therefore the risk of side effects. They should therefore be taken as far apart in time as possible from 
GIOTRIF. This means preferably 6 hours (for medicines taken twice daily) or 12 hours (for medicines taken 
once daily) apart from GIOTRIF:

 Ritonavir, ketoconazole (except in shampoo), itraconazole, erythromycin, nelfinavir, 
saquinavir - used to treat different kinds of infections. 

 Verapamil, quinidine, amiodarone - used to treat heart conditions. 
 Cyclosporine A, tacrolimus - medicines that affect your immune system. 

The following medicines may reduce the effectiveness of GIOTRIF:
 Carbamazepine, phenytoin, phenobarbital - used to treat seizures.
 St. John’s wort (Hypericum perforatum), a herbal medicine to treat depression.
 Rifampicin, an antibiotic used to treat tuberculosis.

Ask your doctor if you are unsure of when to take these medicines.

GIOTRIF may increase the blood levels of other medicines including but not limited to:
 Sulfasalazine, used to treat inflammation/infection.
 Rosuvastatin, used for lowering cholesterol.

Tell your doctor before taking these medicines together with GIOTRIF.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Pregnancy
You should avoid becoming pregnant while taking this medicine. If you could become pregnant, you should 
use adequate birth control methods during treatment and for at least 1 month after taking the last dose of this 
medicine. This is because there may be a risk that an unborn baby is harmed.



71

If you become pregnant while receiving this medicine, you should immediately inform your doctor. Your 
doctor will decide with you whether treatment should be continued or not.

If you plan to become pregnant after taking the last dose of this medicine, you should ask your doctor for 
advice as your body may not have fully eliminated this medicine. 

Breast-feeding
Do not breast-feed while taking this medicine as a risk to the breast-fed child cannot be excluded.

Driving and using machines
If you experience treatment-related symptoms affecting your eye sight (e.g. redness and/or irritation of the 
eye, dry eye, tearing, light-sensitivity) or your ability to concentrate and react, it is recommended that you do 
not drive or use machines until the side effect disappears (see section 4 Possible side effects).

GIOTRIF contains lactose
This medicine contains a sugar called lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take GIOTRIF

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure.

Dosage
The recommended dose is 40 mg each day. 

Your doctor may adjust (increase or decrease) your dose depending on how well you tolerate this medicine. 

When to take GIOTRIF
 It is important to take this medicine without food
 Take this medicine at least 1 hour before eating, or
 If you have already eaten, wait at least 3 hours before taking this medicine.
 Take this medicine once daily about the same time each day. This makes it easier to remember to 

take this medicine.
 Do not break, chew or crush the tablet.
 Swallow the tablet whole with a glass of still water.

GIOTRIF is to be taken by mouth. If you have difficulties swallowing the tablet, dissolve it in a glass of still 
water. No other liquids should be used. Drop the tablet into the water without crushing it, and occasionally 
stir for up to 15 min until the tablet is broken up into very small particles. Drink the liquid straight away. 
Then fill the glass again with water and drink it to make sure all medicine is taken. 

If you are not able to swallow and have a gastric tube your doctor might suggest that the medicine is given to 
you via the tube.

If you take more GIOTRIF than you should
Contact your doctor or pharmacist immediately. You may experience increased side effects and your doctor 
may interrupt your treatment and provide supportive care.

If you forget to take GIOTRIF
 If your next scheduled dose is more than 8 hours away, take the missed dose as soon as you 

remember. 
 If your next scheduled dose is due within 8 hours, skip the missed dose and take your next dose at 

the usual time. Then carry on taking your tablets at regular times as usual. 
Do not take a double dose (two tablets instead of one at the same time) to make up for a missed dose.



72

If you stop taking GIOTRIF
Do not stop taking this medicine without first consulting your doctor. It is important to take this medicine 
every day, as long as your doctor prescribes it for you. If you do not take this medicine as prescribed by your 
doctor your cancer may grow again.

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

4. Possible side effects

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

Contact your doctor as soon as possible if you suffer from any of the serious side effects listed below. In 
some cases your doctor may need to interrupt treatment and reduce your dose or stop treatment:

 Diarrhoea (very common, may affect more than 1 in 10 people). 
Diarrhoea lasting more than 2 days or more severe diarrhoea may lead to fluid loss (common, may 
affect up to 1 in 10 people), low blood potassium (common) and worsening kidney function 
(common). Diarrhoea can be treated. At the first signs of diarrhoea drink plenty of fluids. Contact 
your doctor immediately and start appropriate antidiarrhoeal treatment as soon as possible. You 
should have antidiarrhoeal medicine available prior to taking GIOTRIF. 

 Skin rash (very common).
It is important to treat the rash early. Tell your doctor if a rash starts.  If treatment for rash is not 
working and the rash is getting more severe (for example, you have peeling or blistering of the skin)
you should notify your doctor immediately, since your doctor may decide to stop your treatment 
with GIOTRIF.  Rash may occur or worsen in areas exposed to sun. Sun protection with protective 
clothing and sunscreen is recommended.

 Inflammation of the lungs (uncommon, may affect up to 1 in 100 people) called “interstitial lung 
disease”. 
Tell your doctor immediately if you develop new or sudden worsening of shortness of breath, 
possibly with a cough or fever. 

 Eye irritation or inflammation
Eye irritation or inflammation may occur (conjunctivitis/keratoconjunctivitis occurs commonly and 
keratitis uncommonly). Tell your doctor if you have sudden or worsening of eye symptoms such as 
pain or redness or dry eye.

If you experience any of the symptoms above, contact your doctor as soon as possible.

The following other side effects have also been reported:

Very common side effects (may affect more than 1 in 10 people):
 Mouth sores and inflammation
 Nail infection
 Decreased appetite
 Bleeding from the nose
 Nausea
 Vomiting
 Itching
 Dry skin

Common side effects (may affect up to 1 in 10 people):
 Pain, redness, swelling or peeling of the skin of your hands and feet



73

 Increased levels of the liver enzymes (aspartate aminotransferase and alanine aminotransferase) in 
blood tests.

 Inflammation of the lining of the bladder with burning sensations during urination and frequent, 
urgent need to urinate (cystitis)

 Abnormal taste sensations (dysgeusia)
 Stomach pain, indigestion, heartburn
 Lip inflammation
 Decreased weight
 Runny nose 
 Muscle spasms
 Fever
 Nail problems

Uncommon side effects (may affect up to 1 in 100 people):
 Inflammation of the pancreas (pancreatitis)
 Occurrence of a tear in the wall of your stomach or intestines (gastrointestinal perforation)

Rare side effects (may affect up to 1 in 1,000 people):
 Severe blistering or peeling of skin (suggestive of Stevens-Johnson syndrome and toxic epidermal 

necrolysis)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 
in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store GIOTRIF

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

Do not use this medicine after the expiry date which is stated on the carton, the pouch and the blister after 
EXP. The expiry date refers to the last day of that month.

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

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What GIOTRIF contains 
- The active substance is afatinib. Each film-coated tablet contains 50 mg of afatinib (as dimaleate).
- The other ingredients are lactose monohydrate, microcrystalline cellulose (E460), colloidal anhydrous 

silica (E551), crospovidone type A, magnesium stearate (E470b), hypromellose  (E464), 
macrogol 400, titanium dioxide (E171), talc (E553b), polysorbate 80 (E433), indigo carmine (E132) 
aluminium lake. 

What GIOTRIF looks like and contents of the pack
GIOTRIF 50 mg film-coated tablets are dark blue and oval shaped. They are debossed with the code “T50” 
on one side and the Boehringer Ingelheim company logo on the other.

GIOTRIF film-coated tablets are available in packs containing 1, 2 or 4 perforated unit dose blisters. Each 
blister contains 7 x 1 film-coated tablets and is packed in an aluminium pouch together with a desiccant 
sachet that should not be swallowed.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


74

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



75

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti Filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211



76

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in {MM/YYYY}

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET