IRESSA 250mg tablets medication leaflet

IRESSA 250 mg film-coated tablets

Each tablet contains 250 mg of gefitinib.

Each tablet contains 163.5 mg of lactose (as monohydrate).

Each tablet contains 3.86 mg of sodium.

For the full list of excipients, see section 6.1.

Film-coated tablets (tablet).

Tablets are brown, round, biconvex, impressed with “IRESSA 250” on one side and plain on the other.

IRESSA is indicated as monotherapy for the treatment of adult patients with locally advanced ormetastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (see section4.4).

Treatment with IRESSA should be initiated and supervised by a physician experienced in the use ofanti-cancer therapies.

The recommended posology of IRESSA is one 250 mg tablet once a day. If a dose is missed, it shouldbe taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient shouldnot take the missed dose. Patients should not take a double dose (two doses at the same time) to makeup for a forgotten dose.

The safety and efficacy of IRESSA in children and adolescents aged less than 18 years has not beenestablished. There is no relevant use of gefitinib in the paediatric population in the indication of

Patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to cirrhosis haveincreased plasma concentrations of gefitinib. These patients should be closely monitored for adverseevents. Plasma concentrations were not increased in patients with elevated aspartate transaminase(AST), alkaline phosphatase or bilirubin due to liver metastases (see section 5.2).

No dose adjustment is required in patients with impaired renal function at creatinine clearance> 20 ml/min. Only limited data are available in patients with creatinine clearance  20 ml/min andcaution is advised in these patients (see section 5.2).

No dose adjustment is required on the basis of patient age (see section 5.2).

CYP2D6 poor metabolisers

No specific dose adjustment is recommended in patients with known CYP2D6 poor metabolisergenotype, but these patients should be closely monitored for adverse events (see section 5.2).

Dose adjustment due to toxicity

Patients with poorly tolerated diarrhoea or skin adverse reactions may be successfully managed byproviding a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg dose(see section 4.8). For patients unable to tolerate treatment after a therapy interruption, gefitinib shouldbe discontinued and an alternative treatment should be considered.

The tablet may be taken orally with or without food, at about the same time each day. The tablet can beswallowed whole with some water or if dosing of whole tablets is not possible, tablets may beadministered as a dispersion in water (non-carbonated). No other liquids should be used. Withoutcrushing it, the tablet should be dropped in half a glass of drinking water. The glass should be swirledoccasionally, until the tablet is dispersed (this may take up to 20 minutes). The dispersion should bedrunk immediately after dispersion is complete (i.e. within 60 minutes). The glass should be rinsedwith half a glass of water, which should also be drunk. The dispersion can also be administeredthrough a naso-gastric or gastrostomy tube.

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

Breast-feeding (see section 4.6).

When considering the use of IRESSA as a treatment for locally advanced or metastatic NSCLC, it isimportant that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumoursample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma)sample may be used.

Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFRmutation status of tumours or ctDNA should be used to avoid false negative or false positivedeterminations (see section 5.1).

Interstitial lung disease (ILD)

Interstitial lung disease (ILD) which may be acute in onset, has been observed in 1.3% of patientsreceiving gefitinib, and some cases have been fatal (see section 4.8). If patients experience worseningof respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and thepatient should be promptly investigated. If ILD is confirmed, IRESSA should be discontinued and thepatient treated appropriately.

In a Japanese pharmacoepidemiological case control study in 3,159 patients with NSCLC receivinggefitinib or chemotherapy who were followed up for 12 weeks, the following risk factors fordeveloping ILD (irrespective of whether the patient received IRESSA or chemotherapy) wereidentified: smoking, poor performance status (PS ≥ 2), CT scan evidence of reduced normal lung(≤ 50%), recent diagnosis of NSCLC (< 6 months), pre-existing ILD, older age (≥ 55 years old) andconcurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seenpredominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafterthe relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8). Risk of mortality among patients whodeveloped ILD on IRESSA or chemotherapy was higher in patients with the following risk factors:smoking, CT scan evidence of reduced normal lung (≤ 50%), pre-existing ILD, older age (≥ 65 yearsold), and extensive areas adherent to pleura (≥ 50%).

Hepatotoxicity and liver impairment

Liver function test abnormalities (including increases in alanine aminotransferase, aspartateaminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis (see section 4.8).

There have been isolated reports of hepatic failure which in some cases led to fatal outcomes.

Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in thepresence of mild to moderate changes in liver function. Discontinuation should be considered ifchanges are severe.

Impaired liver function due to cirrhosis has been shown to lead to increased plasma concentrations ofgefitinib (see section 5.2).

CYP3A4 inducers may increase metabolism of gefitinib and decrease gefitinib plasma concentrations.

Therefore, concomitant administration of CYP3A4 inducers (e.g. phenytoin, carbamazepine,rifampicin, barbiturates or herbal preparations containing St John’s wort/Hypericum perforatum) mayreduce efficacy of the treatment and should be avoided (see section 4.5).

In individual patients with CYP2D6 poor metaboliser genotype, treatment with a potent CYP3A4inhibitor might lead to increased plasma levels of gefitinib. At initiation of treatment with a CYP3A4inhibitor, patients should be closely monitored for gefitinib adverse reactions (see section 4.5).

International normalised ratio (INR) elevations and/or bleeding events have been reported in somepatients taking warfarin together with gefitinib (see section 4.5). Patients taking warfarin and gefitinibconcomitantly should be monitored regularly for changes in prothrombin time (PT) or INR.

Medicinal products that cause significant sustained elevation in gastric pH, such as proton-pumpinhibitors and h2-antagonists may reduce bioavailability and plasma concentrations of gefitinib and,therefore, may reduce efficacy. Antacids if taken regularly close in time to administration of gefitinibmay have a similar effect (see sections 4.5 and 5.2).

Data from phase II clinical trials, where gefitinib and vinorelbine have been used concomitantly,indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine.

IRESSA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

IRESSA contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially‘sodium-free.’

Further precautions for use

Patients should be advised to seek medical advice immediately if they experience severe or persistentdiarrhoea, nausea, vomiting or anorexia as these may indirectly lead to dehydration. These symptomsshould be managed as clinically indicated (see section 4.8).

Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eyeinflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referredpromptly to an ophthalmology specialist.

If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and ifsymptoms do not resolve, or if symptoms recur on reintroduction of gefitinib, permanentdiscontinuation should be considered.

In a phase I/II trial studying the use of gefitinib and radiation in paediatric patients, with newlydiagnosed brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases(1 fatal) of Central Nervous System (CNS) haemorrhages were reported from 45 patients enrolled. Afurther case of CNS haemorrhage has been reported in a child with an ependymoma from a trial withgefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receivinggefitinib has not been established.

Gastrointestinal perforation has been reported in patients taking gefitinib. In most cases this isassociated with other known risk factors, including concomitant medications such as steroids or

NSAIDS, underlying history of GI ulceration, age, smoking or bowel metastases at sites of perforation.

The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via

CYP2D6.

Active substances that may increase gefitinib plasma concentrations

In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do notsuggest any clinical consequences to this in vitro finding.

Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administrationwith potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, proteaseinhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increasemay be clinically relevant since adverse reactions are related to dose and exposure. The increase mightbe higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment withitraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib inhealthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 thepatient should be closely monitored for gefitinib adverse reactions.

There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of thisenzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisersby about 2-fold (see section 5.2). If concomitant treatment with a potent CYP2D6 inhibitor is initiated,the patient should be closely monitored for adverse reactions.

Active substances that may reduce gefitinib plasma concentrations

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinibplasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal productsthat induce CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John’s wort/

Hypericum perforatum) should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer)in healthy volunteers reduced mean gefitinib AUC by 83% (see section 4.4).

Substances that cause significant sustained elevation in gastric pH may reduce gefitinib plasmaconcentrations and thereby reduce the efficacy of gefitinib. High doses of short-acting antacids mayhave a similar effect if taken regularly close in time to administration of gefitinib. Concomitantadministration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥ 5resulted in a reduced mean gefitinib AUC by 47% in healthy volunteers (see section 4.4 and 5.2).

Active substances that may have their plasma concentrations altered by gefitinib

In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. In a clinical trial inpatients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35%increase in exposure to metoprolol. Such an increase might potentially be relevant for CYP2D6substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered incombination with gefitinib, a dose modification of the CYP2D6 substrate should be consideredespecially for products with a narrow therapeutic window.

Gefitinib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding isunknown.

Other potential interactions

INR elevations and/or bleeding events have been reported in some patients concomitantly takingwarfarin (see section 4.4).

Women of childbearing potential must be advised not to get pregnant during therapy.

There are no data from the use of gefitinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). The potential risk for humans is unknown. IRESSA should notbe used during pregnancy unless clearly necessary.

It is not known whether gefitinib is secreted in human milk. Gefitinib and metabolites of gefitinibaccumulated in milk of lactating rats (see section 5.3). Gefitinib is contraindicated duringbreast-feeding and therefore breast-feeding must be discontinued while receiving gefitinib therapy (seesection 4.3).

During treatment with gefitinib, asthenia has been reported. Therefore, patients who experience thissymptom should be cautious when driving or using machines.

In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials(2462 IRESSA-treated patients), the most frequently reported adverse drug reactions (ADRs),occurring in more than 20% of the patients, are diarrhoea and skin reactions (including rash, acne, dryskin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible.

Approximately 8% of patients had a severe ADR (common toxicity criteria (CTC) grade 3 or 4).

Approximately 3% of patients stopped therapy due to an ADR.

Interstitial lung disease (ILD) has occurred in 1.3% of patients, often severe (CTC grade 3-4). Caseswith fatal outcomes have been reported.

The safety profile presented in Table 1 is based on the gefitinib clinical development programme andpostmarketed experience. Adverse reactions have been assigned to the frequency categories in Table 1where possible based on the incidence of comparable adverse event reports in a pooled dataset fromthe ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-treated patients).

Frequencies of occurrence of undesirable effects are defined as: very common (≥ 1/10); common(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare(< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions

Adverse reactions by system organ class and frequency

Metabolism and nutrition Very common Anorexia mild or moderatedisorders (CTC grade 1 or 2)

Eye disorders Common Conjunctivitis, blepharitis, anddry eye*, mainly mild (CTCgrade 1)

Uncommon Corneal erosion, reversible andsometimes in association withaberrant eyelash growth

Keratitis (0.12%)

Vascular disorders Common Haemorrhage, such as epistaxisand haematuria

Respiratory, thoracic and Common Interstitial lung disease (1.3%),mediastinal disorders often severe (CTC grade 3-4).

Cases with fatal outcomes havebeen reported

Gastrointestinal disorders Very common Diarrhoea, mainly mild ormoderate (CTC grade 1 or 2)

Vomiting, mainly mild ormoderate (CTC grade 1 or 2)

Nausea, mainly mild (CTCgrade 1)

Stomatitis, predominantly mildin nature (CTC grade 1)

Common Dehydration, secondary todiarrhoea, nausea, vomiting oranorexia

Dry mouth*, predominantlymild (CTC grade 1)

Uncommon Pancreatitis

Gastrointestinal perforation

Hepatobiliary disorders Very common Elevations in alanineaminotransferase, mainly mildto moderate

Common Elevations in aspartateaminotransferase, mainly mildto moderate

Elevations in total bilirubin,mainly mild to moderate

Uncommon Hepatitis**

Skin and subcutaneous tissue Very common Skin reactions, mainly a mild ordisorders moderate (CTC grade 1 or 2)pustular rash, sometimes itchywith dry skin, including skinfissures, on an erythematousbase

Common Nail disorder

Alopecia

Allergic reactions (1.1%),includingangioedema and urticaria

Uncommon Palmar-plantarerythrodysaesthesia syndrome

Rare Bullous conditions includingtoxic epidermal necrolysis,

Stevens Johnson syndrome anderythema multiforme

Cutaneous vasculitis

Renal and urinary disorders Common Asymptomatic laboratoryelevations in blood creatinine

Proteinuria

Cystitis

Rare Haemorrhagic cystitis

General disorders and Very common Asthenia, predominantly mildadministration site conditions (CTC grade 1)

Common Pyrexia

The frequency of adverse drug reactions relating to abnormal laboratory values is based on patients with achange from baseline of 2 or more CTC grades in the relevant laboratory parameters.

*This adverse reaction can occur in association with other dry conditions (mainly skin reactions) seen withgefitinib.

**This includes isolated reports of hepatic failure which in some cases led to fatal outcomes.

Interstitial lung disease (ILD)

In the INTEREST trial, the incidence of ILD type events was 1.4% (10) patients in the gefitinib groupversus 1.1% (8) patients in the docetaxel group. One ILD-type event was fatal, and this occurred in apatient receiving gefitinib.

In the ISEL trial, the incidence of ILD-type events in the overall population was approximately 1% inboth treatment arms. The majority of ILD-type events reported was from patients of Asian ethnicityand the ILD incidence among patients of Asian ethnicity receiving gefitinib therapy and placebo wasapproximately 3% and 4% respectively. One ILD-type event was fatal, and this occurred in a patientreceiving placebo.

In a post-marketing surveillance study in Japan (3350 patients) the reported rate of ILD-type events inpatients receiving gefitinib was 5.8%. The proportion of ILD-type events with a fatal outcome was38.6%.

In a phase III open-label clinical trial (IPASS) in 1217 patients comparing IRESSA tocarboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced

NSCLC in Asia, the incidence of ILD-type events was 2.6% on the IRESSA treatment arm versus1.4% on the carboplatin/paclitaxel treatment arm.

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

There is no specific treatment in the event of overdose of gefitinib. However, in phase I clinical trials,a limited number of patients were treated with daily doses of up to 1000 mg. An increase of frequencyand severity of some adverse reactions was observed, mainly diarrhoea and skin rash. Adversereactions associated with overdose should be treated symptomatically; in particular severe diarrhoeashould be managed as clinically indicated. In one study a limited number of patients were treatedweekly with doses from 1500 mg to 3500 mg. In this study IRESSA exposure did not increase withincreasing dose, adverse events were mostly mild to moderate in severity, and were consistent with theknown safety profile of IRESSA.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors; ATC code: L01EB01

Mechanism of action and pharmacodynamic effects

The epidermal growth factor (EGF) and its receptor (EGFR [HER1; ErbB1]) have been identified askey drivers in the process of cell growth and proliferation for normal and cancer cells. EGFRactivating mutation within a cancer cell is an important factor in promotion of tumour cell growth,blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes ofmetastasis.

Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinaseand is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosinekinase domain regardless of line of therapy. No clinically relevant activity has been shown in patientswith known EGFR mutation-negative tumours.

The common EGFR activating mutations (Exon 19 deletions; L858R) have robust response datasupporting sensitivity to gefitinib; for example a progression free survival HR (95% CI) of 0.489(0.336, 0.710) for gefitinib vs. doublet chemotherapy [WJTOG3405]. Gefitinib response data is moresparse in patients whose tumours contain the less common mutations; the available data indicates that

G719X, L861Q and S7681 are sensitising mutations; and T790M alone or exon 20 insertions alone areresistance mechanisms.

Most NSCLC tumours with sensitising EGFR kinase mutations eventually develop resistance to

IRESSA treatment, with a median time to disease progression of 1 year. In about 60% of cases,resistance is associated with a secondary T790M mutation for which T790M targeted EGFR TKIs maybe considered as a next line treatment option. Other potential mechanisms of resistance that have beenreported following treatment with EGFR signal blocking agents include: bypass signalling such as

HER2 and MET gene amplification and PIK3CA mutations. Phenotypic switch to small cell lungcancer has also been reported in 5-10% of cases.

Circulating Tumour DNA (ctDNA)

In the IFUM trial, mutation status was assessed in tumour and ctDNA samples derived from plasma,using the Therascreen EGFR RGQ PCR kit (Qiagen). Both ctDNA and tumour samples were evaluablefor 652 patients out of 1060 screened. The objective response rate (ORR) in those patients who weretumour and ctDNA mutation positive was 77% (95% CI: 66% to 86%) and in those who were tumouronly mutation positive 60% (95% CI: 44% to 74%).

Table 2 Summary of baseline mutation status for tumour and ctDNA samples in all screenedpatients evaluable for both samples

Measure Definition IFUM rate IFUM% (CI) N

Sensitivity Proportion of tumour M+ that are 65.7 (55.8, 74.7) 105

M+ by ctDNA

Specificity Proportion of tumour M- that are M- 99.8 (99.0, 100.0) 547by ctDNA)

These data are consistent with the pre-planned exploratory Japanese subgroup analysis in IPASS (Goto2012). In that study ctDNA derived from serum, not plasma was used for EGFR mutation analysisusing the EGFR Mutation Test Kit (DxS) (N= 86). In that study, sensitivity was 43.1%, specificity was100%.

First line treatment

The randomised phase III first line IPASS study was conducted in patients in Asia1 with advanced(stage IIIB or IV) NSCLC of adenocarcinoma histology who were ex-light smokers (ceased smoking> 15 years ago and smoked < 10 pack years) or never smokers (see Table 3).

1China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand.

Table 3 Efficacy outcomes for gefitinib versus carboplatin/paclitaxel from the IPASS study

Population N Objective Primary endpoint Overallresponse rates Progression free survival survivala,band 95% CI for (PFS) a,bdifferencebetweentreatmentsa

Overall 1217 43.0% vs 32.2% HR 0.74 HR 0.90[5.3%, 16.1%] [0.65, 0.85] [0.79, 1.02]5.7 m vs 5.8 m 18.8 m vs 17. 4mp<0.0001 p=0.1087

Population N Objective Primary endpoint Overallresponse rates Progression free survival survivala,band 95% CI for (PFS) a,bdifferencebetweentreatmentsa

EGFR 261 71.2% vs 47.3% HR 0.48 HR 1.00mutation-positive [12.0%, 34.9%] [0.36, 0.64] [0.76, 1.33]9.5 m vs 6.3 m 21.6 m vs 21.9 mp<0.0001

EGFR 176 1.1% vs 23.5% HR 2.85 HR 1.18mutation-negative [-32.5%, -13.3%] [2.05, 3.98] [0.86, 1.63]1.5 m vs 5.5 m 11.2 m vs 12.7 mp<0.0001

EGFR mutation- 780 43.3% vs 29.2% HR 0.68 HR 0.82unknown [7.3%, 20.6%] [0.58 to 0.81] [0.70 to 0.96]6.6 m vs 5.8 m 18.9 m vs. 17.2 mp<0.0001a Values presented are for IRESSA versus carboplatin/paclitaxel.b “m” is medians in months. Numbers in square brackets are 95% confidence intervals for HR

N Number of patients randomised.

HR Hazard ratio (hazard ratios <1 favour IRESSA)

Quality of life outcomes differed according to EGFR mutation status. In EGFR mutation-positivepatients, significantly more IRESSA-treated patients experienced an improvement in quality of life andlung cancer symptoms vs. carboplatin/paclitaxel (see Table 4).

Table 4 Quality of life outcomes for gefitinib versus carboplatin/paclitaxel from the IPASS study

Population N FACT-L QoL improvement LCS symptom improvementratea rate a %%

Overall 1151 (48.0% vs 40.8%) (51.5% vs 48.5%)p=0.0148 p=0.3037

EGFR 259 (70.2% vs 44.5%) (75.6% vs 53.9%)mutation-positive p<0.0001 p=0.0003

EGFR 169 (14.6% vs 36.3%) (20.2% vs 47.5%)mutation-negative p=0.0021 p=0.0002

Trial outcome index results were supportive of FACT-L and LCS resultsa Values presented are for IRESSA versus carboplatin/paclitaxel.

N Number of patients evaluable for quality of life analyses

QoL Quality of life

FACT-LFunctional assessment of cancer therapy-lung

LCS Lung cancer subscale

In the IPASS trial, IRESSA demonstrated superior PFS, ORR, QoL and symptom relief with nosignificant difference in overall survival compared to carboplatin/paclitaxel in previously untreatedpatients, with locally advanced or metastatic NSCLC, whose tumours harboured activating mutationsof the EGFR tyrosine kinase.

Pretreated patients

The randomised phase III INTEREST study was conducted in patients with locally advanced ormetastatic NSCLC who had previously received platinum-based chemotherapy. In the overallpopulation, no statistically significant difference between gefitinib and docetaxel (75 mg/m2) wasobserved for overall survival, progression free survival and objective response rates (see Table 5).

Table 5 Efficacy outcomes for gefitinib versus docetaxel from the INTEREST study

Population Objective Progression free survivalab Primary

N response rates endpoint overalland 95% CI for survivalabdifferencebetweentreatmentsa

Overall 1466 9.1% vs 7.6% HR 1.04 HR 1.020[-1.5%, 4.5%] [0.93,1.18] [0.905, 1.150] c2.2 m vs 2.7 m 7.6 m vs 8.0 mp=0.4658 p=0.7332

EGFR 44 42.1% vs 21.1% HR 0.16 HR 0.83mutation-positive [-8.2%, 46.0%] [0.05, 0.49] [0.41, 1.67]7.0 m vs 4.1 m 14.2 m vs 16.6 mp=0.0012 p=0.6043

EGFR 253 6.6% vs 9.8% HR 1.24 HR 1.02mutation- negative [-10.5%, pct. 4.4%] [0.94,1.64] [0.78, 1.33]1.7 m vs 2.6 m 6.4 m vs 6.0 mp=0.1353 p=0.9131

Asiansc 323 19.7% vs 8.7% HR 0.83 HR 1.04[3.1 %, 19.2%] [0.64,1.08] [0.80, 1.35]2.9 m vs 2.8 m 10.4 m vs 12.2 mp=0.1746 p=0.7711

Non-Asians 1143 6.2% vs 7.3% HR 1.12 HR 1.01[-4.3%, 2.0%] [0.98, 1.28] [0.89, 1.14]2.0 m vs 2.7 m 6.9 m vs 6.9 mp=0.1041 p=0.9259a Values presented are for IRESSA versus docetaxel.

b “m” is medians in months. Numbers in square brackets are 96% confidence interval for overall survival

HR in the overall population, or otherwise 95% confidence intervals for HRc Confidence interval entirely below non-inferiority margin of 1.154

N Number of patients randomised.

HR Hazard ratio (hazard ratios <1 favour IRESSA)

Figures 1 and 2 Efficacy outcomes in subgroups of non-Asian patients in the INTEREST study(N patients = Number of patients randomised)

Overall Survival

N patients1143 Overall27 EGFR Mutation+222 EGFR Mutation-133 Never-smoker1010 Ever-smoker600 Adenocarcinoma543 Non-adenocarcinoma369 Female774 Male0.5 1.0 1.5 2.0

Hazard Ratio (Gefitinib versus Docetaxel) and 95% CI

Unadjusted analysis PP population for clinical factors ITT population for biomarker factors

Progression-free Survival

ORR (%)

N patients Gefitinib v. Docetaxel1143 6.2 v. 7.3 Overall27 42.9 v. 20.0 EGFR Mutation+222 5.5 v. 9.1 EGFR Mutation133 23.7 v. 13.3 Never-smoker1010 3.9 v. 6.5 Ever-smoker600 9.4 v. 9.4 Adenocarcinoma543 2.8 v. 5.0 Non-adenocarcinoma369 9.8 v. 13.1 Female774 4.4 v. 4.6 Male0 0.5 1.0 1.5 2.0

Hazard Ratio (Gefitinib versus Docetaxel) and 95% CI

Unadjusted analysis EFR population

The randomised phase III ISEL study was conducted in patients with advanced NSCLC who hadreceived 1 or 2 prior chemotherapy regimens and were refractory or intolerant to their most recentregimen. Gefitinib plus best supportive care was compared to placebo plus best supportive care.

IRESSA did not prolong survival in the overall population. Survival outcomes differed by smokingstatus and ethnicity (see Table 6).

Table 6 Efficacy outcomes for gefitinib versus placebo from the ISEL study

Population Objective Time to treatment failureab Primary

N response rates endpoint overalland 95% CI for survivalabcdifferencebetweentreatmentsa

Overall 1692 8.0% vs 1.3% HR 0.82 HR 0.89[4.7%, 8.8%] [0.73, 0.92] [0.77,1.02]3.0 m vs 2.6 m 5.6 m vs 5.1 mp=0.0006 p=0.0871

EGFR 26 37.5% vs 0% HR 0.79 HR NCmutation- positive [-15.1%, 61.4%] [0.20, 3.12]10.8 m vs 3.8m NR vs 4.3 mp=0.7382

EGFR 189 2.6% vs 0% HR 1.10 HR 1.16mutation- negative [-5.6%, 7.3%] [0.78, 1.56] [0.79, 1.72]2.0 m vs 2.6 m 3.7 m vs 5.9 mp=0.5771 p=0.4449

Never smoker 375 18.1% vs 0% HR 0.55 HR 0.67[12.3 %, 24.0%] [0.42, 0.72] [0.49, 0.92]5.6 m vs 2.8 m 8.9 m vs 6.1 mp<0.0001 p=0.0124

Ever smoker 1317 5.3% vs 1.6% HR 0.89 HR 0.92[1.4%, 5.7%] [0.78, 1.01] [0.79, 1.06]2.7 m vs 2.6 m 5.0 m vs 4.9 mp=0.0707 p=0.2420

Asiansd 342 12.4% vs 2.1% HR 0.69 HR 0.66[4.0%, 15.8%] [0.52, 0.91] [0.48, 0.91]4.4 m vs 2.2 m 9.5 m vs 5.5 mp=0.0084 p=0.0100

Non-Asians 1350 6.8% vs 1.0% HR 0.86 HR 0.92[3.5%, 7.9%] [0.76, 0.98] [0.80, 1.07]2.9 m vs 2.7 m 5.2 m vs 5.1 mp=0.0197 p=0.2942a Values presented are for IRESSA versus placebo.

b “m” is medians in months. Numbers in square brackets are 95% confidence intervals for HRc Stratified log-rank test for overall; otherwise cox proportional hazards modeld Asian ethnicity excludes patients of Indian origin and refers to the racial origin of a patient group and notnecessarily their place of birth

N Number of patients randomised

NC Not calculated for overall survival HR as the number of events is too few

NR Not reached

HR Hazard ratio (hazard ratios <1 favour IRESSA)

The IFUM study was a single-arm, multicentre study conducted in Caucasian patients (n=106) withactivating, sensitising EGFR mutation positive NSCLC to confirm that the activity of gefitinib issimilar in Caucasian and Asian populations. The ORR according to investigator review was 70% andthe median PFS was 9.7 months. These data are similar to those reported in the IPASS study.

EGFR mutation status and clinical characteristics

Clinical characteristics of never smoker, adenocarcinoma histology, and female gender have beenshown to be independent predictors of positive EGFR mutation status in a multivariate analysis of786 Caucasian patients from gefitinib studies* (see Table 7). Asian patients also have a higherincidence of EGFR mutation-positive tumours.

Table 7 Summary of multivariate logistic regression analysis to identify factors thatindependently predicted for the presence of EGFR mutations in 786 Caucasian patients*

Factors that p-value Odds of EGFR Positive predictive value (9.5% of thepredicted for mutation overall population are EGFRpresence of mutation-positive (M+))

EGFR mutation

Smoking status <0.0001 6.5 times higher in never 28/70 (40%) of never smokers are M+smokers than 47/716 (7%) of ever smokers are M+ever-smokers

Histology <0.0001 4.4 times higher in 63/396 (16%) of patients withadenocarcinoma than in adenocarcinoma histology are M+non-adenocarcinoma 12/390 (3%) of patients withnon-adenocarcinoma histology are M+

Gender 0.0397 1.7 times higher in 40/235 (17%) of females are M+females than males 35/551 (6%) of males are M+

*from the following studies: INTEREST, ISEL, INTACT 1&2, IDEAL 1&2, INVITE

Following oral administration of gefitinib, absorption is moderately slow and peak plasmaconcentrations of gefitinib typically occur at 3 to 7 hours after administration. Mean absolutebioavailability is 59% in cancer patients. Exposure to gefitinib is not significantly altered by food. In atrial in healthy volunteers where gastric pH was maintained above pH 5, gefitinib exposure wasreduced by 47%, likely due to impaired solubility of gefitinib in the stomach (see sections 4.4 and 4.5).

Gefitinib has a mean steady-state volume of distribution of 1400 l indicating extensive distribution intotissue. Plasma protein binding is approximately 90%. Gefitinib binds to serum albumin and alpha1-acid glycoprotein.

In vitro data indicate that gefitinib is a substrate for the membrane transport protein P-gp.

In vitro data indicate that CYP3A4 and CYP2D6 are the major P450 isozyme involved in the oxidativemetabolism of gefitinib.

In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. Gefitinib shows noenzyme induction effects in animal studies and no significant inhibition (in vitro) of any othercytochrome P450 enzyme.

Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in excretaand 8 metabolites in plasma. The major metabolite identified was O-desmethyl gefitinib, which is14-fold less potent than gefitinib at inhibiting EGFR stimulated cell growth and has no inhibitoryeffect on tumour cell growth in mice. It is therefore considered unlikely that it contributes to theclinical activity of gefitinib.

The formation of O-desmethyl gefitinib has been shown, in vitro, to be via CYP2D6. The role of

CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthyvolunteers genotyped for CYP2D6 status. In poor metabolisers no measurable levels of O-desmethylgefitinib were produced. The levels of exposure to gefitinib achieved in both the extensive and thepoor metaboliser groups were wide and overlapping but the mean exposure to gefitinib was 2-foldhigher in the poor metaboliser group. The higher average exposures that could be achieved byindividuals with no active CYP2D6 may be clinically relevant since adverse effects are related to doseand exposure.

Gefitinib is excreted mainly as metabolites via the faeces, with renal elimination of gefitinib andmetabolites accounting for less than 4% of the administered dose.

Gefitinib total plasma clearance is approximately 500 ml/min and the mean terminal half-life is41 hours in cancer patients. Administration of gefitinib once daily results in 2- to 8-fold accumulation,with steady state exposures achieved after 7 to 10 doses. At steady state, circulating plasmaconcentrations are typically maintained within a 2- to 3-fold range over the 24-hour dosing interval.

From analyses of population pharmacokinetic data in cancer patients, no relationships were identifiedbetween predicted steady-state trough concentration and patient age, body weight, gender, ethnicity orcreatinine clearance (above 20 ml/min).

In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severehepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase inexposure in all groups compared with healthy controls. An average 3.1-fold increase in exposure togefitinib in patients with moderate and severe hepatic impairment was observed. None of the patientshad cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinicalrelevance since adverse experiences are related to dose and exposure to gefitinib.

Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normalhepatic function, or moderate or severe hepatic impairment (classified according to baseline Common

Toxicity Criteria grades for AST, alkaline phosphatase and bilirubin) due to liver metastases. It wasshown that following daily administration of 250 mg gefitinib, time to steady-state, total plasmaclearance (CmaxSS) and steady-state exposure (AUC24SS) were similar for the groups with normal andmoderately impaired hepatic function. Data from 4 patients with severe hepatic impairment due to livermetastases suggested that steady-state exposures in these patients are also similar to those in patientswith normal hepatic function.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to theclinical exposure levels and with possible relevance to clinical use were as follows:

 Corneal epithelia atrophy and corneal translucencies Renal papillary necrosis Hepatocellular necrosis and eosinophilic sinusoidal macrophage infiltration

Data from non-clinical (in vitro) studies indicate that gefitinib has the potential to inhibit the cardiacaction potential repolarisation process (e.g. QT interval). Clinical experience has not shown a causalassociation between QT prolongation and gefitinib.

A reduction in female fertility was observed in the rat at a dose of 20 mg/kg/day.

Published studies have shown that genetically modified mice, lacking expression of EGFR, exhibitdevelopmental defects, related to epithelial immaturity in a variety of organs including the skin,gastrointestinal tract and lung. When gefitinib was administered to rats during organogenesis, therewere no effects on embryofoetal development at the highest dose (30 mg/kg/day). However, in therabbit, there were reduced foetal weights at 20 mg/kg/day and above. There were nocompound-induced malformations in either species. When administered to the rat throughout gestationand parturition, there was a reduction in pup survival at a dose of 20 mg/kg/day.

Following oral administration of C-14 labelled gefitinib to lactating rats 14 days post-partum,concentrations of radioactivity in milk were 11-19 fold higher than in blood.

Gefitinib showed no genotoxic potential.

A 2-year carcinogenicity study in rats resulted in a small but statistically significant increasedincidence of hepatocellular adenomas in both male and female rats and mesenteric lymph nodehaemangiosarcomas in female rats at the highest dose (10 mg/kg/day) only. The hepatocellularadenomas were also seen in a 2-year carcinogenicity study in mice, which demonstrated a smallincreased incidence of this finding in male mice at the mid dose, and in both male and female mice atthe highest dose. The effects reached statistical significance for the female mice, but not for the males.

At no-effect levels in both mice and rats there was no margin in clinical exposure. The clinicalrelevance of these findings is unknown.

The results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicitypotential.

Lactose monohydrate

Microcrystalline cellulose (E460)

Croscarmellose sodium

Povidone (K29-32) (E1201)

Sodium laurilsulfate

Magnesium stearate

Hypromellose (E464)

Macrogol 300

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Not applicable.

4 years.

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

PVC/Aluminium perforated blister containing 10 tablets or PVC/Aluminium non-perforated blistercontaining 10 tablets.

Three blisters are combined with an aluminium foil laminate over-wrap in a carton.

Pack size of 30 film-coated tablets. Not all pack sizes may be marketed.

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

AstraZeneca AB

SE-151 85

Södertälje

Sweden

EU/1/09/526/001 perforated blister

EU/1/09/526/002 non perforated blister

Date of first authorisation: 24 June 2009

Date of latest renewal: 23 April 2014

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