Gilotrif

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, Gilotrif should be withheld and supportive care initiated.

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

Incompatibilities

Not applicable.

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 as well as stomatitis and paronychia (see also Table 3, 4 and 5). Overall, dose reduction led to a lower frequency of common adverse reactions.

In patients treated with once daily Gilotrif 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 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.

Tabulated list of adverse reactions

Table 2 summarises the frequencies of ADRs from all NSCLC trials and from post-marketing experience with daily Gilotrif 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

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 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 Gilotrif-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

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

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

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 Gilotrif 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 Gilotrif.

Description of selected adverse reactions

Very common ADRs in Gilotrif-treated patients occurring in at least 10% of patients in trial LUX-Lung 8 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 5.

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

* 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 Gilotrif 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 Gilotrif.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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 Gilotrif 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 Gilotrif.

Therapeutic indications

Gilotrif 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.

Pharmacotherapeutic group

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

Gilotrif 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 Gilotrif 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 Gilotrif 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.

LUX-Lung 6

The efficacy and safety of Gilotrif 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 Gilotrif 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)

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

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

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

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 Gilotrif 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 Gilotrif.

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

a values presented for Gilotrif 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 Gilotrif 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 Gilotrif® 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. Gilotrif significantly improved PFS and ORR in EGFR mutation positive patients compared to gefitinib. The efficacy results are summarized in Table 9.

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

1OS results based on primary OS analysis as of April 2016 at event rates of 109 (68.1%) and 117 (73.6%) in the Gilotrif 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.

Gilotrif in patients with NSCLC of squamous histology

The efficacy and safety of Gilotrif 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 Gilotrif 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 Gilotrif 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 Gilotrif vs erlotinib in LUX-Lung 8, based on primary analysis of OS, including all randomized patients

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).

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

a values presented for Gilotrif 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

Pharmacokinetic properties

Absorption

Following oral administration of Gilotrif, 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 Gilotrif. 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 AUC,ss was observed when food was consumed within 3 hours before or 1 hour after taking Gilotrif. Therefore, food should not be consumed for at least 3 hours before and at least 1 hour after taking Gilotrif.

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.). Gilotrif 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 Gilotrif. 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. The pharmacokinetics of afatinib have not been studied in subjects with severe (Child Pugh C) hepatic dysfunction.

Population pharmacokinetic analysis in special populations

A population pharmacokinetic analysis was performed in 927 cancer patients (764 with NSCLC) receiving Gilotrif 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,ss) was increased by 26% for a 42 kg patient (2.5th percentile) and decreased by 22% for a 95 kg patient (97.5th percentile) relative to a patient weighing 62 kg (median body weight of patients in the overall patient population).

Gender

Female patients had a 15% higher plasma exposure (AUC,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,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.

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.

Name of the medicinal product

Qualitative and quantitative composition

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 Gilotrif. 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. 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 Gilotrif. 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. 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 Gilotrif treatment. Patients with severe skin reactions may also require temporary interruption of therapy, dose reduction , 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.

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. 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 Gilotrif for treatment of NSCLC. ILD-like adverse reactions were reported in 0.7% of patients treated with Gilotrif 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, Gilotrif should be permanently discontinued and appropriate treatment initiated as necessary.

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. Dose interruption may become necessary in patients who experience worsening of liver function. In patients who develop severe hepatic impairment while taking Gilotrif, treatment should be 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.

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.

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.

Effects on ability to drive and use machines

Gilotrif 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 which may affect patients ability to drive or use machines.

Dosage (Posology) and method of administration

Treatment with Gilotrif 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 Gilotrif therapy.

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.

Gilotrif 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 Gilotrif as outlined in Table 1.

Table 1: Dose adjustment information for adverse reactions

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 Gilotrif 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, Gilotrif should be discontinued and appropriate treatment initiated as necessary.

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 Gilotrif 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 Gilotrif.

Special populations

Patients with renal impairment

Exposure to afatinib was found to be increased in patients with moderate or severe renal impairment. 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 Gilotrif dose if not tolerated.

Gilotrif 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. 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.

Paediatric population

There is no relevant use of Gilotrif 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.

Special precautions for disposal and other handling

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