Giotrif

Afatinib dimaleate.

One film-coated tablet contains 20 mg, 30 mg, 40 mg or 50 mg afatinib (as dimaleate).
Excipient with known effect: GIOTRIF 20 mg: One film-coated tablet contains 118 mg lactose (as monohydrate).
GIOTRIF 30 mg: One film-coated tablet contains 176 mg lactose (as monohydrate).
GIOTRIF 40 mg: One film-coated tablet contains 235 mg lactose (as monohydrate).
GIOTRIF 50 mg: One film-coated tablet contains 294 mg lactose (as monohydrate).
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, Microcrystalline cellulose (E460), Colloidal anhydrous silica (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 (E132) aluminium hydroxide.

Pharmacotherapeutic Group: Antineoplastic agents, protein kinase inhibitors. ATC Code: L01EB03.
Pharmacology: Pharmacodynamics: 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 (1200.32): In the first-line setting, the efficacy and safety of GIOTRIF in patients with EGFR mutation-positive locally advanced or metastatic NSCLC (stage IIIB or IV) were assessed in a global, randomised, multicenter, 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 and Tables 1 and 2.
LUX-Lung 6 (1200.34): 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 1 and 2 (LUX-Lung 3 and 6). Table 2 shows outcomes in the subgroups of patients with two common EGFR mutations - Del 19 and L858R. (See Figure 1 and Table 1 and Table 2.)

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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 3). Mean scores over time for overall quality of life, global health status and physical, role, and cognitive functioning were significantly better for GIOTRIF. (See Table 3.)

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LUX-Lung 2 (1200.22): 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 (1200.123): LUX-Lung 7 is a randomised, global, open label Phase IIb trial investigating the efficacy and safety of GIOTRIF in patients with locally advanced or metastatic lung adenocarcinoma (stage IIIB or IV) with EGFR mutations in the first-line setting. Patients were screened for the presence of activating EGFR mutations (Del 19 and/or L858R) using the TheraScreen EGFR RGQ PCR Kit, Qiagen Manchester Ltd). Patients (N=319) were randomised (1:1) to receive GIOTRIF 40 mg orally once daily (N=160) or gefitinib 250 mg orally once daily (N=159). Randomisation was stratified according to EGFR mutation status (Del 19; L858R) and presence of brain metastases (yes; no).
Among the patients randomised, 62% were female, the median age was 63 years, 16% of patients had brain metastases, the baseline ECOG performance status was 0 (31%) or 1 (69%), 57% were Asian and 43% were non-Asian. Patients had a tumour sample with an EGFR mutation categorised as either exon 19 deletion (58%) or exon 21 L858R substitutions (42%).
The co-primary endpoints 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 4. (See Table 4.)

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The PFS hazard ratio for patients with DEL 19 mutations and L858R mutations was 0.76 (95% CI [0.55, 1.06]; p=0.1071), and 0.71 (95% CI [0.47, 1.06]; p=0.0856) respectively for afatinib vs gefitinib.
Analysis of GIOTRIF's efficacy in EGFR TKI naïve patients with tumours harbouring uncommon EGFR Mutations (LUX-Lung 2, -3, and -6): In three clinical trials of GIOTRIF with prospective tumour genotyping (Phase 3 trials LUX-Lung 3 and - 6, and single arm Phase 2 trial LUX-Lung 2), an analysis was conducted of data from a total of 75 TKI-naive patients with advanced (stage IIIb-IV) lung adenocarcinomas harbouring uncommon EGFR mutations, which were defined as all mutations other than Del 19 and L858R mutations. Patients were treated with GIOTRIF 40 mg (all three trials) or 50 mg (LUX-Lung 2) orally once daily.
In patients with tumours harbouring either G719X (N=18), L861Q (N=16), or S768I substitution mutation (N=8), the confirmed ORR was 72.2%, 56.3%, 75.0%, respectively, and the median duration of response was 13.2 months, 12.9 months and 26.3 months, respectively.
In patients with tumours harbouring exon 20 insertions (N=23) the confirmed ORR was 8.7% and the median duration of response was 7.1 months. In patients with tumours harbouring de-novo T790M mutations (N=14) the confirmed ORR was 14.3% and the median duration of response was 8.3 months.
GIOTRIF in patients with NSCLC of squamous histology: LUX-Lung 8 (1200.125): The efficacy and safety of GIOTRIF as second-line treatment for patients with advanced NSCLC of squamous histology was investigated in a 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%).
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 5. (See Figure 2 and Table 5.)

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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).

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PFS benefit was accompanied by improvement in disease-related symptoms and delayed time to deterioration (see Table 6).

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Paediatric population: A Phase I/II open-label, dose escalation, multicentre trial evaluated the safety and efficacy of GIOTRIF in paediatric patients aged 2 to less than 18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology. A total of 17 patients were treated in the dose finding part of the trial. In the maximum tolerated dose (MTD) expansion part of the trial, 39 patients selected by biomakers of ErbB pathway deregulation received GIOTRIF at a dose of 18 mg/m2/day. In this expansion part, no objective responses were observed in 38 patients, including 6 patients with refractory high grade glioma (HGG), 4 patients with diffuse intrinsic pontine glioma (DIPG), 8 patients with ependymoma and 20 patients with other histologies. One patient with a neural-glial tumour of the brain with a CLIP2-EGFR gene fusion had a confirmed partial response (see information on paediatric use under Dosage & Administration). The adverse reaction profile of GIOTRIF in paediatric patients was consistent with the safety profile seen in adults.
Pharmacokinetics: Absorption: Following oral administration of GIOTRIF, C_max of afatinib were observed approximately 2 to 5 hours post dose. C_max and AUC_0-∞ 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% (C_max) and 39% (AUC_0-∞), 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 AUC_τ,ss was observed when food was consumed within 3 hours before or 1 hour after taking GIOTRIF. Therefore, food should not be consumed for at least 3 hours before and at least 1 hour after taking GIOTRIF (see Dosage & Administration and Interactions).
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 afatinib 15 mg, 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 (AUC_0-∞) and 2.11-fold (C_max). 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% (C_max) and 122% (AUC_0-tz) in comparison to their healthy controls. Subjects with severe renal impairment (n=8; eGFR 15-29 mL/min/1.73m², according to the MDRD formula) had an exposure of 122% (C_max) and 150% (AUC_0-tz) in comparison to their healthy controls. Based on this trial and population pharmacokinetic analysis of data derived from clinical trials in various tumour types, it is concluded, that adjustments to the starting dose in patients with mild (eGFR 60-89 mL/min/1.73m²), 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" as follows and Dosage & Administration). 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" as follows). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment (see Dosage & Administration). The pharmacokinetics of afatinib have not been studied in subjects with severe (Child Pugh C) hepatic dysfunction (see Precautions).
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 (AUC_τ,ss) was increased by 26% for a 42 kg patient (2.5^th percentile) and decreased by 22% for a 95 kg patient (97.5^th percentile) relative to a patient weighing 62 kg (median body weight of patients in the overall patient population).
Gender: Female patients had a 15% higher plasma exposure (AUC_τ,ss, body weight corrected) than 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 (AUC_τ,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.
Paediatric population: After administration of 18 mg/m2 afatinib, the steady-state exposure (AUC and Cmax) in paediatric patients aged 2 to less tan 18 years was comparable to that observed in adults given 40-50 mg afatinib (see also information on paediatric use under Dosage & Administration).
Other information on drug-drug interactions: Interactions with drug uptake transport systems: In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transporters are considered unlikely.
Interactions with Cytochrome P450 (CYP) enzymes: In humans it was found that enzyme-catalyzed metabolic reactions play a negligible role for 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.
Toxicology: Preclinical Safety Data: Oral administration of single doses to mice and rats indicated a low acute toxic potential of afatinib. In oral repeated-dose studies for up to 26 weeks in rats or 52 weeks in minipigs the main effects were identified in the skin (dermal changes, epithelial atrophy and folliculitis in rats), the gastrointestinal tract (diarrhoea, erosions in the stomach, epithelial atrophy in rats and minipigs) and the kidneys (papillary necrosis in rats).
Depending on the finding, these changes occurred at exposures below, in the range of or above clinically relevant levels. Additionally, in various organs pharmacodynamically mediated atrophy of epithelia was observed in both species.
Reproduction toxicity: Based on the mechanism of action, all EGFR targeting medicinal products including GIOTRIF have the potential to cause foetal harm. The embryo-foetal development studies performed on afatinib revealed no indication of teratogenicity. The respective total systemic exposure (AUC) was either slightly above (2.2 times in rats) or below (0.3 times in rabbits) compared with levels in patients.
Radiolabelled afatinib administered orally to rats on Day 11 of lactation was excreted in the breast milk of the dams.
A fertility study in male and female rats up to the maximum tolerated dose revealed no significant impact on fertility. The total systemic exposure (AUC_0-24) in male and female rats was in the range or less than that observed in patients (1.3 times and 0.51 times, respectively).
A study in rats up to the maximum tolerated doses revealed no significant impact on pre-/postnatal development. The highest total systemic exposure (AUC_0-24) in female rats was less than that observed in patients (0.23 times).
Phototoxicity: An in vitro 3T3 test showed that afatinib may have phototoxicity potential.
Carcinogenicity: Carcinogenicity studies have not been conducted with GIOTRIF.

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); Locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy (see Pharmacology: Pharmacodynamics under Actions).

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 Precautions).
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 Interactions and Pharmacology: Pharmacokinetics under Actions).
GIOTRIF treatment should be continued until disease progression or until no longer tolerated by the patient (see Table 7 as follows).
Dose escalation: A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/day 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 7 (see Precautions and Adverse Reactions). (See Table 7.)

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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 Precautions).
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 Interactions).
Special populations: Patients with renal impairment: Exposure to afatinib was found to be increased in patients with moderate or severe renal impairment (see Pharmacology: Pharmacokinetics under Actions). 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 Pharmacology: Pharmacokinetics under Actions). 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 Precautions).
Paediatric population: There is no relevant use of GIOTRIF in the paediatric population in the indication of NSCLC.
Treatment of children or adolescents with GIOTRIF was not supported by a clinical trial conducted in paediatric patients and with other conditions (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions). Safety and efficacy have not been established.
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 noncarbonated drinking water. No other liquids should be used. The tablet should be dropped into the water without crushing it, and stirred occasionally for up to 15 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.

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

Hypersensitivity to afatinib or to any of the excipients listed in Description).

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 Adverse Reactions). 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.
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. Anti-diarrhoeal 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 Dosage & Administration). Patients who become dehydrated may require administration of intravenous electrolytes and fluids.
Skin-related adverse events: Rash/acne has been reported in patients treated with this medicinal product (see Adverse Reactions). 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 Dosage & Administration), additional therapeutic intervention, and referral to a specialist with expertise in managing these dermatologic effects.
Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment with this medicinal product should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions (see Adverse Reactions).
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 Pharmacology: Pharmacokinetics under Actions). 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 Dosage & Administration).
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 Adverse Reactions). Dose interruption may become necessary in patients who experience worsening of liver function (see Dosage & Administration). In patients who develop severe hepatic impairment while taking GIOTRIF, treatment should be discontinued.
Gastrointestinal perforations: Gastrointestinal perforation, including fatalities, has been reported during treatment with GIOTRIF in 0.2% of patients across all randomized controlled clinical trials. In the majority of cases, gastrointestinal perforation was associated with other known risk factors, including concomitant medications such as corticosteroids, NSAIDs, or anti-angiogenic agents, an underlying history of gastrointestinal ulceration, underlying diverticular disease, age, or bowel metastases at sites of perforation. In patients who develop gastrointestinal perforation while taking GIOTRIF, treatment should be permanently discontinued.
Keratitis: Symptoms such as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment 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 Adverse Reactions).
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 that 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 Interactions).
Lactose: This medicinal product contains lactose. Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on the 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 Adverse Reactions) which may affect patients ability to drive or use machines.

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 Pharmacology: Toxicology: Preclinical Safety Data under Actions). 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 Pharmacology: Toxicology: Preclinical Safety Data under Actions).
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, the patient 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 Pharmacology: Toxicology: Preclinical Safety Data under Actions). 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.

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 8 as follows. The most frequent ADRs were diarrhoea and skin related adverse events (see Precautions) as well as stomatitis and paronychia (see also Tables 9, 10 and 11). Overall, dose reduction (see Dosage & Administration) 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 LUX-Lung 3 trial and in 25% of the patients in the LUX-Lung 8 trial. Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0% in LUX-Lung 3 and 3.8% and 2.0% in LUX-Lung 8, respectively.
ILD-like adverse reactions were reported in 0.7% of afatinib treated patients. Bullous, blistering 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 Precautions).
Tabulated list of adverse reactions: Table 8 summarises the frequencies of ADRs pooled 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. (See Table 8.)

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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 9 and 10. (See Table 9 and Table 10.)

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Click on icon to see table/diagram/image

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 Precautions).
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 11. (See Table 11.)

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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 Precautions).
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.

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 (AUC_0-∞)) and 39% (maximum plasma concentration (C_max)). In contrast, when ritonavir was administered simultaneously or 6 hours after 40 mg GIOTRIF, the relative bioavailability of afatinib was 119% (AUC_0-∞) and 104% (C_max) and 111% (AUC_0-∞) and 105% (C_max), 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 Dosage & Administration).
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% (AUC_0-∞) and 22% (C_max) 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 Precautions).
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 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 C_max and 39% in regard to AUC_0-∞. This medicinal product should be administered without food (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Do not store above 30°C.
Store in the original package in order to protect from moisture and light.

Targeted Cancer Therapy

L01EB03 - afatinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.

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