TARCEVA 150mg tablets medication leaflet

Tarceva 25 mg film-coated tablets

Tarceva 100 mg film-coated tablets

Tarceva 150 mg film-coated tablets

Tarceva 25 mg film coated tablets

Each film-coated tablet contains 25 mg erlotinib (as erlotinib hydrochloride).

Tarceva 100 mg film-coated tablets

Each film-coated tablet contains 100 mg erlotinib (as erlotinib hydrochloride).

Tarceva 150 mg film-coated tablets

Each film-coated tablet contains 150 mg erlotinib (as erlotinib hydrochloride).

Tarceva 25 mg film coated tablets

Each 25 mg film-coated tablet contains 27.43 mg Lactose monohydrate.

Tarceva 100 mg film-coated tablets

Each 100 mg film-coated tablet contains 69.21 mg Lactose monohydrate.

Tarceva 150 mg film-coated tablets

Each 150 mg film-coated tablet contains 103.82 mg Lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Tarceva 25 mg film coated tablets

White to yellowish, round, biconvex tablets with ‘T 25’ engraved on one side.

Tarceva 100 mg film-coated tablets

White to yellowish, round, biconvex tablets with ‘T 100’ engraved on one side.

Tarceva 150 mg film-coated tablets

White to yellowish, round, biconvex tablets with ‘T 150’ engraved on one side.

Non-Small Cell Lung Cancer (NSCLC)

Tarceva is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR activating mutations.

Tarceva is also indicated for switch maintenance treatment in patients with locally advanced ormetastatic NSCLC with EGFR activating mutations and stable disease after first-line chemotherapy.

Tarceva is also indicated for the treatment of patients with locally advanced or metastatic NSCLCafter failure of at least one prior chemotherapy regimen. In patients with tumours without EGFRactivating mutations, Tarceva is indicated when other treatment options are not considered suitable.

When prescribing Tarceva, factors associated with prolonged survival should be taken into account.

No survival benefit or other clinically relevant effects of the treatment have been demonstrated inpatients with Epidermal Growth Factor Receptor (EGFR)-IHC negative tumours (see section 5.1).

Pancreatic cancer

Tarceva in combination with gemcitabine is indicated for the treatment of patients with metastaticpancreatic cancer.

When prescribing Tarceva, factors associated with prolonged survival should be taken into account(see sections 4.2 and 5.1).

No survival advantage could be shown for patients with locally advanced disease.

Tarceva treatment should be supervised by a physician experienced in the use of anti-cancer therapies.

Patients with Non-Small Cell Lung Cancer

EGFR mutation testing should be performed in accordance with the approved indications (see section4.1).

The recommended daily dose of Tarceva is 150 mg taken at least one hour before or two hours afterthe ingestion of food.

Patients with pancreatic cancer

The recommended daily dose of Tarceva is 100 mg taken at least one hour before or two hours afterthe ingestion of food, in combination with gemcitabine (see the summary of product characteristics ofgemcitabine for the pancreatic cancer indication). In patients who do not develop rash within the first4 - 8 weeks of treatment, further Tarceva treatment should be re-assessed (see section 5.1).

When dose adjustment is necessary, the dose should be reduced in 50 mg steps (see section 4.4).

Tarceva is available in strengths of 25 mg, 100 mg and 150 mg.

Concomitant use of CYP3A4 substrates and modulators may require dose adjustment (see section 4.5).

Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure wassimilar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared withpatients with adequate hepatic function, caution should be used when administering Tarceva topatients with hepatic impairment. Dose reduction or interruption of Tarceva should be considered ifsevere adverse reactions occur. The safety and efficacy of erlotinib has not been studied in patientswith severe hepatic dysfunction (AST/SGOT and ALT/SGPT> 5 x ULN). Use of Tarceva in patientswith severe hepatic dysfunction is not recommended (see section 5.2).

The safety and efficacy of erlotinib has not been studied in patients with renal impairment (serumcreatinine concentration >1.5 times the upper normal limit). Based on pharmacokinetic data no doseadjustments appear necessary in patients with mild or moderate renal impairment (see section 5.2).

Use of Tarceva in patients with severe renal impairment is not recommended.

The safety and efficacy of erlotinib in the approved indications has not been established in patientsunder the age of 18 years. Use of Tarceva in paediatric patients is not recommended.

Smokers

Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerateddose of Tarceva in NSCLC patients who currently smoke cigarettes was 300 mg. The 300 mg dose didnot show improved efficacy in second line treatment after failure of chemotherapy compared to therecommended 150 mg dose in patients who continue to smoke cigarettes. Safety data were comparablebetween the 300 mg and 150 mg doses; however, there was a numerical increase in the incidence ofrash, interstitial lung disease and diarrhoea, in patients receiving the higher dose of erlotinib. Currentsmokers should be advised to stop smoking (see sections 4.4, 4.5, 5.1 and 5.2).

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

Assessment of EGFR mutation status

When considering the use of Tarceva as a first line or maintenance treatment for locally advanced ormetastatic NSCLC, it is important that the EGFR mutation status of a patient is determined.

A validated, robust, reliable and sensitive test with a prespecified positivity threshold anddemonstrated utility for the determination of EGFR mutation status, using either tumor DNA derivedfrom a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, shouldbe performed according to local medical practice.

If a plasma-based cfDNA test is used and the result is negative for activating mutations, perform atissue test wherever possible due to the potential for false negative results from a plasma-based test.

Smokers

Current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokersas compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant(see sections 4.2, 4.5, 5.1 and 5.2).

Interstitial Lung Disease

Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reporteduncommonly in patients receiving Tarceva for treatment of non-small cell lung cancer (NSCLC),pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, theincidence of ILD (0.8%) was the same in both the placebo and Tarceva groups. In a meta-analysis of

NSCLC randomised controlled clinical trials (excluding phase I and single-arm phase II studies due tolack of control groups), the incidence of ILD-like events was 0.9% on Tarceva compared to 0.4% inpatients in the control arms. In the pancreatic cancer study in combination with gemcitabine, theincidence of ILD-like events was 2.5% in the Tarceva plus gemcitabine group versus 0.4% in theplacebo plus gemcitabine treated group. Reported diagnoses in patients suspected of having ILD-likeevents included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitialpneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory

Distress Syndrome (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days toseveral months after initiating Tarceva therapy. Confounding or contributing factors such asconcomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease,metastatic lung disease, or pulmonary infections were frequent. A higher incidence of ILD(approximately 5% with a mortality rate of 1.5%) is seen among patients in studies conducted in

Japan.

In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms suchas dyspnoea, cough and fever, Tarceva therapy should be interrupted pending diagnostic evaluation.

Patients treated concurrently with erlotinib and gemcitabine should be monitored carefully for thepossibility to develop ILD-like toxicity. If ILD is diagnosed, Tarceva should be discontinued andappropriate treatment initiated as necessary (see section 4.8).

Diarrhoea, dehydration, electrolyte imbalance and renal failure

Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50% ofpatients on Tarceva and moderate or severe diarrhoea should be treated with e.g. loperamide. In somecases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps.

Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistentdiarrhoea, nausea, anorexia, or vomiting associated with dehydration, Tarceva therapy should beinterrupted and appropriate measures should be taken to treat the dehydration (see section 4.8). Therehave been rare reports of hypokalaemia and renal failure (including fatalities). Some cases weresecondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others wereconfounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or casesleading to dehydration, particularly in groups of patients with aggravating risk factors (especiallyconcomitant chemotherapy and other medications, symptoms or diseases or other predisposingconditions including advanced age), Tarceva therapy should be interrupted and appropriate measuresshould be taken to intensively rehydrate the patients intravenously. In addition, renal function andserum electrolytes including potassium should be monitored in patients at risk of dehydration.

Serious cases of drug induced liver injury (DILI) including hepatitis, acute hepatitis and hepatic failure(including fatalities) have been reported during use of Tarceva. Risk factors may include pre-existingliver disease or concomitant hepatotoxic medications. Periodic liver function testing is recommendedduring treatment with Tarceva. The frequency of monitoring of liver function should be increased inpatients with pre-existing hepatic impairment or biliary obstruction. Prompt clinical evaluation andmeasurement of liver function tests should be performed in patients who report symptoms that mayindicate liver injury. Tarceva dosing should be interrupted if changes in liver function are severe (seesection 4.8). Tarceva is not recommended for use in patients with severe hepatic dysfunction.

Gastrointestinal perforation

Patients receiving Tarceva are at increased risk of developing gastrointestinal perforation, which wasobserved uncommonly (including some cases with a fatal outcome). Patients receiving concomitantanti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who haveprior history of peptic ulceration or diverticular disease are at increased risk. Tarceva should bepermanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).

Bullous and exfoliative skin disorders

Bullous, blistering and exfoliative skin conditions have been reported, including very rare casessuggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal(see section 4.8). Tarceva treatment should be interrupted or discontinued if the patient developssevere bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disordersshould be tested for skin infection and treated according to local management guidelines.

Ocular disorders

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, treatmentwith Tarceva should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks ofcontinuing treatment should be carefully considered. Tarceva should be used with caution in patientswith a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factorfor keratitis and ulceration.Very rare cases of corneal perforation or ulceration have been reportedduring use of Tarceva (see section 4.8).

Potent inducers of CYP3A4 may reduce the efficacy of erlotinib whereas potent inhibitors of CYP3A4may lead to increased toxicity. Concomitant treatment with these types of agents should be avoided(see section 4.5).

Other forms of interactions

Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter thepH of the upper Gastro-Intestinal (GI) tract, like proton pump inhibitors, H2 antagonists and antacids,may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of Tarceva whenco-administered with such agents is not likely to compensate for the loss of exposure. Combination oferlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration oferlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely.

Therefore, concomitant administration of these combinations should be avoided (see section 4.5). Ifthe use of antacids is considered necessary during treatment with Tarceva, they should be taken atleast 4 hours before or 2 hours after the daily dose of Tarceva.

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicine

This medicine contains less than 1 mmol sodium (less than 23 mg) per tablet, that is to say Tarceva isessentially ‘sodium -free’.

Interaction studies have only been performed in adults.

Erlotinib and other CYP substrates

Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as wellas a strong inhibitor of glucuronidation by UGT1A1 in vitro.

The physiological relevance of the strong inhibition of CYP1A1 is unknown due to the very limitedexpression of CYP1A1 in human tissues.

When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinibexposure [AUC] increased significantly by 39%, while no statistically significant change in Cmax wasfound. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and

Cmax, respectively. The clinical relevance of this increase has not been established. Caution should beexercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined witherlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.

Pre-treatment or co-administration of Tarceva did not alter the clearance of the prototypical CYP3A4substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability ofmidazolam by up to 24%. In another clinical study, erlotinib was shown not to affect pharmacokineticsof the concomitantly administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with theclearance of other CYP3A4 substrates are therefore unlikely.

The inhibition of glucuronidation may cause interactions with medicinal products which are substratesof UGT1A1 and exclusively cleared by this pathway. Patients with low expression levels of UGT1A1or genetic glucuronidation disorders (e.g. Gilbert’s disease) may exhibit increased serumconcentrations of bilirubin and must be treated with caution.

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and toa lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and

CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potentialinteractions may occur with active substances which are metabolised by, or are inhibitors or inducersof, these enzymes.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasmaconcentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orallytwice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase of erlotinib exposure (86%of AUC and 69% of Cmax). Therefore, caution should be used when erlotinib is combined with a potent

CYP3A4 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole, voriconazole), proteaseinhibitors, erythromycin or clarithromycin. If necessary the dose of erlotinib should be reduced,particularly if toxicity is observed.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinibplasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mgorally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% decrease in the medianerlotinib AUC. Co-administration of rifampicin with a single 450 mg dose of Tarceva resulted in amean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg Tarceva dose in the absence ofrifampicin treatment. Co-administration of Tarceva with CYP3A4 inducers should therefore beavoided. For patients who require concomitant treatment with Tarceva and a potent CYP3A4 inducersuch as rifampicin an increase in dose to 300 mg should be considered while their safety (includingrenal and liver functions and serum electrolytes) is closely monitored, and if well tolerated for morethan 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Reducedexposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St. John’s

Wort (hypericum perforatum). Caution should be observed when these active substances are combinedwith erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be consideredwhen possible.

Erlotinib and coumarin-derived anticoagulants

Interaction with coumarin-derived anticoagulants including warfarin leading to increased International

Normalized Ratio (INR) and bleeding events, which in some cases were fatal, have been reported inpatients receiving Tarceva. Patients taking coumarin-derived anticoagulants should be monitoredregularly for any changes in prothrombin time or INR.

Erlotinib and statins

The combination of Tarceva and a statin may increase the potential for statin-induced myopathy,including rhabdomyolysis, which was observed rarely.

Erlotinib and smokers

Results of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced

AUCinf, Cmax and plasma concentration at 24 hours, respectively, after administration of Tarceva insmokers as compared to non-smokers. Therefore, patients who are still smoking should be encouragedto stop smoking as early as possible before initiation of treatment with Tarceva, as plasma erlotinibconcentrations are reduced otherwise. Based on the data from the CURRENTS study, no evidence wasseen for any benefit of a higher erlotinib dose of 300 mg when compared with the recommended doseof 150 mg in active smokers. Safety data were comparable between the 300 mg and 150 mg doses;however, there was a numerical increase in the incidence of rash, interstitial lung disease anddiarrhoea, in patients receiving the higher dose of erlotinib (see sections 4.2, pct. 4.4, 5.1 and 5.2).

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate for the P-glycoprotein active substance transporter. Concomitant administrationof inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or alteredelimination of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not beenestablished. Caution should be exercised in such situations.

Erlotinib and medicinal products altering pH

Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter thepH of the upper Gastro-Intestinal (GI) tract may alter the solubility of erlotinib and hence itsbioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI),decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%,respectively. There was no change to Tmax or half-life. Concomitant administration of Tarceva with300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximumconcentrations [Cmax] by 33% and 54%, respectively. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for this loss of exposure. However, when

Tarceva was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d.,erlotinib exposure [AUC] and maximum concentrations [Cmax] decreased only by 15% and 17%,respectively. The effect of antacids on the absorption of erlotinib has not been investigated butabsorption may be impaired, leading to lower plasma levels. In summary, the combination of erlotinibwith proton pump inhibitors should be avoided. If the use of antacids is considered necessary duringtreatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of

Tarceva. If the use of ranitidine is considered, it should be used in a staggered manner; i.e. Tarcevamust be taken at least 2 hours before or 10 hours after ranitidine dosing.

Erlotinib and Gemcitabine

In a Phase Ib study, there were no significant effects of gemcitabine on the pharmacokinetics oferlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.

Erlotinib and Carboplatin/Paclitaxel

Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib withcarboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10.6%. Although statisticallysignificant, the magnitude of this difference is not considered to be clinically relevant. In clinicalpractice, there may be other co-factors leading to an increased exposure to carboplatin like renalimpairment. There were no significant effects of carboplatin or paclitaxel on the pharmacokinetics oferlotinib.

Erlotinib and Capecitabine

Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination withcapecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in

Cmax when compared with values observed in another study in which erlotinib was given as singleagent. There were no significant effects of erlotinib on the pharmacokinetics of capecitabine.

Erlotinib and proteasome inhibitors

Due to the working mechanism, proteasome inhibitors including bortezomib may be expected toinfluence the effect of EGFR inhibitors including erlotinib. Such influence is supported by limitedclinical data and preclinical studies showing EGFR degradation through the proteasome.

There are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shownno evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancycan not be excluded as rat and rabbit studies have shown increased embryo/foetal lethality (seesection 5.3). The potential risk for humans is unknown.

Women of childbearing potential must be advised to avoid pregnancy while on Tarceva. Adequatecontraceptive methods should be used during therapy, and for at least 2 weeks after completingtherapy. Treatment should only be continued in pregnant women if the potential benefit to the motheroutweighs the risk to the foetus.

It is not known whether erlotinib is excreted in human milk. No studies have been conducted to assessthe impact of Tarceva on milk production or its presence in breast milk. As the potential for harm tothe nursing infant is unknown, mothers should be advised against breast-feeding while receiving

Tarceva and for at least 2 weeks after the final dose.

Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on thefertility can not be excluded as animal studies have shown effects on reproductive parameters (seesection 5.3). The potential risk for humans is unknown.

No studies on the effects on the ability to drive and use machines have been performed; howevererlotinib is not associated with impairment of mental ability.

Safety evaluation of Tarceva is based on the data from more than 1500 patients treated with at leastone 150 mg dose of Tarceva monotherapy and more than 300 patients who received Tarceva 100 or150 mg in combination with gemcitabine.

Non-small cell lung cancer (Tarceva administered as monotherapy)

First-Line Treatment of Patients with EGFR Mutations

In an open-label, randomised phase III study, ML20650 conducted in 154 patients, the safety of

Tarceva for first-line treatment of NSCLC patients with EGFR activating mutations was assessed in 75patients.

The most frequent adverse drug reactions (ADRs) seen in patients treated with Tarceva in study

ML20650 were rash and diarrhoea, most were Grade 1/2 in severity and manageable withoutintervention. Full grade and incidence information for rash and diarrhoea for all clinical studies isavailable in the ‘Description of selected adverse reactions’ section below.

In two other double-blind, randomised, placebo-controlled Phase III studies BO18192 (SATURN) and

BO25460 (IUNO); Tarceva was administered as maintenance after first-line chemotherapy. Thesestudies were conducted in a total of 1532 patients with advanced, recurrent or metastatic NSCLCfollowing first-line standard platinum-based chemotherapy.

The most frequent ADRs seen in patients treated with Tarceva in studies BO18192 and BO25460 wererash and diarrhoea.

Second and Further Line Treatment

In a randomised double-blind study (BR.21; Tarceva administered as second line therapy), rash anddiarrhoea were the most commonly reported adverse drug reactions (ADRs). Most were Grade 1/2 inseverity and manageable without intervention. The median time to onset of rash was 8 days, and themedian time to onset of diarrhoea was 12 days.

Pancreatic cancer (Tarceva administered concurrently with gemcitabine)

The most common adverse reactions in pivotal study PA.3 in pancreatic cancer patients receiving

Tarceva 100 mg plus gemcitabine were fatigue, rash and diarrhoea. The median time to onset of rashand diarrhoea was 10 days and 15 days, respectively.

The incidence of ADRs from clinical trials and the post marketing setting reported with Tarceva aloneor in combination with chemotherapy are summarised in Table 1. Adverse drug reactions are listed by

MedDRA system organ class. The corresponding frequency category for each adverse drug reaction isbased on the following convention: 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 beestimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Summary of ADRs from clinical trials and the post-marketing setting per frequency category:

Very common infection*

Very common anorexia, weight decreased

Very common depression

Very common neuropathy, headache

Very common keratoconjunctivitis sicca

Common keratitis, conjunctivitis

Uncommon eyelash changes*

Very rare corneal perforations, corneal ulcerations, uveitis

Very common dyspnoea, cough

Common epistaxis

Uncommon interstitial lung disease*

Very common diarrhoea*, nausea, vomiting, stomatitis, abdominal pain, dyspepsia,flatulence

Common gastro-intestinal bleeding*

Uncommon gastro-intestinal perforations*

Rare pneumatosis intestinalis

Very common liver function test abnormalities*

Rare hepatic failure*, hepatitis

Not known (Cannot be acute hepatitisestimated from theavailable data)

Very common rash*, pruritus

Common alopecia, dry skin, paronychia, folliculitis, acne/dermatitis acneiform, skinfissures

Uncommon hirsutism, eyebrow changes, brittle and loose nails, mild skin reactionssuch as hyperpigmentation

Rare palmar plantar erythrodysaesthesia syndrome

Very rare Stevens-Johnson syndrome/Toxic epidermal necrolysis*

Common renal insufficiency

Uncommon nephritis, proteinuria

Very common fatigue, pyrexia, rigors

*For additional details, see section 'Description of selected adverse reactions' below.

Rash includes dermatitis acneiform. In general, rash manifests as a mild or moderate erythematous andpapulopustular rash, which may occur or worsen in sun exposed areas. For patients who are exposed tosun, protective clothing, and/or use of sunscreen (e.g. mineral-containing) may be advisable.

Diarrhoea can lead to dehydration, hypokalemia and renal failure. It includes fatalities (see section4.4).

Table 2: A summary of the incidence and grade of rash and diarrhoea observed in each clinical study

Study Indication Rash (%) Diarrhoea (%)

Grade Action taken Grade Action taken

Any 3 4 Discon1 Mod2 Any 3 4 Discon1 Mod2

ML20650 NSCLC 80 9 0 1 11 57 4 0 1 7

BO18192 NSCLC 49.2 6.0 0 1 8.3 20.3 1.8 0 <1 3

BO25460 NSCLC 39.4 5.0 0 0 5.6 24.2 2.5 0 0 2.8

BR.21 NSCLC 75 9 1 6 54 6 1 1

PA.3 Pancreatic - 5 1 2 - 5 1 2cancer1 Discontinuation2 Dose modification

Infection

This can be severe infections with or without neutropenia, including pneumonia, sepsis, and cellulitis.

Eyelash changes

Changes include in-growing eyelashes, excessive growth and thickening of the eyelashes.

Interstitial lung disease (ILD)

ILD includes fatalities in patients receiving Tarceva for treatment of NSCLC or other advanced solidtumours (see section 4.4). A higher incidence has been observed in patients in Japan (see section 4.4)

Gastro-intestinal (GI) bleeding

GI bleeding includes fatalities (see section 4.4). In clinical studies, some cases have been associatedwith concomitant warfarin administration and some with concomitant NSAID administration (seesection 4.5). Gastro-intestinal perforations also include fatalities (see section 4.4).

Liver function test abnormalities

Abnormalities include increased alanine aminotransferase [ALT], aspartate aminotransferase [AST]and bilirubin. Cases were mainly mild to moderate in severity, transient in nature or associated withliver metastases.

Hepatic failure

This includes fatalities. Risk factors may include pre-existing liver disease or concomitant hepatotoxicmedications (see section 4.4).

Stevens-Johnson syndrome/Toxic epidermal necrolysis

This includes fatalities (see section 4.4).

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

Single oral doses of Tarceva up to 1000 mg erlotinib in healthy subjects, and up to 1600 mg in cancerpatients have been tolerated. Repeated twice daily doses of 200 mg in healthy subjects were poorlytolerated after only a few days of dosing. Based on the data from these studies, severe adversereactions such as diarrhoea, rash and possibly increased activity of liver aminotransferases may occurabove the recommended dose.

In case of suspected overdose, Tarceva should be withheld and symptomatic treatment initiated.

Pharmacotherapeutic group: antineoplastic agent protein kinase inhibitor, ATC code: L01EB02

Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1(EGFR also known as HER1) tyrosine kinase inhibitor. Erlotinib potently inhibits the intracellularphosphorylation of EGFR. EGFR is expressed on the cell surface of normal cells and cancer cells. Innon-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.

EGFR mutations may lead to constitutive activation of anti-apoptotic and proliferation signalingpathways. The potent effectiveness of erlotinib in blocking EGFR-mediated signalling in these EGFRmutation positive tumours is attributed to the tight binding of erlotinib to the ATP-binding site in themutated kinase domain of the EGFR. Due to the blocking of downstream-signaling, the proliferationof cells is stopped, and cell death is induced through the intrinsic apoptotic pathway. Tumourregression is observed in mouse models of enforced expression of these EGFR activating mutations.

First-line Non-Small Cell Lung Cancer (NSCLC) therapy for patients with EGFR activating mutations(Tarceva administered as monotherapy)

The efficacy of Tarceva in first-line treatment of patients with EGFR activating mutations in NSCLCwas demonstrated in a phase III, randomised, open-label trial (ML20650, EURTAC). This study wasconducted in Caucasian patients with metastatic or locally advanced NSCLC (stage IIIB and IV) whohave not received previous chemotherapy or any systemic antitumour therapy for their advanceddisease and who present mutations in the tyrosine kinase domain of the EGFR (exon 19 deletion orexon 21 mutation). Patients were randomised 1:1 to receive Tarceva 150 mg daily or up to 4 cycles ofplatinum based doublet chemotherapy.

The primary endpoint was investigator assessed PFS. The efficacy results are summarized in Table 3.

Figure 1: Kaplan-Meier curve for investigator assessed PFS in trial ML20650 (EURTAC) (April 2012cut-off)

Table 3: Efficacy results of Tarceva versus chemotherapy in trial ML20650 (EURTAC)

Tarceva Chemo- Hazard Ratio p-valuetherapy (95% CI)

Pre-planned n=77 n=76

Interim

Analysis Primary endpoint:

(35% OS Progression Free Survivalmaturity) (PFS, median in months)*(n=153) Investigator Assessed ** 9.4 5.2 0.42 p<0.0001[0.27-0.64]

Cut-off date: Aug 2010 Independent Review ** 10.4 5.4 0.47 p=0.003[0.27-0.78]

Best Overall Response Rate(CR/PR) 54.5% 10.5% p<0.0001

Overall Survival (OS)(months) 22.9 18.8 0.80[0.47-1.37] p=0.4170

Exploratory

Analysis n=86 n=87(40% OS PFS (median in months), 0.37maturity) Investigator assessed 9.7 5.2 [0.27-0.54] p<0.0001(n=173) Best Overall Response Rate(CR/PR) 58.1% 14.9% p<0.0001

Cut-off date: Jan 2011

OS (months) 19.3 19.5 1.04[0.65-1.68] p=0.8702

Updated n=86 n=87

Analysis(62% OS PFS (median in months) 10.4 5.1 0.34 p<0.0001maturity) [0.23-0.49](n=173)

OS*** (months) 22.9 20.8 0.93

Cut-off date: April 2012 [0.64-1.36] p=0.7149

CR=complete response; PR=partial response

* A 58% reduction in the risk of disease progression or death was observed

** Overall concordance rate between investigator and IRC assessment was 70%

*** A high crossover was observed with 82% of the patients in the chemotherapy arm receiving subsequent therapy with an

EGFR tyrosine kinase inhibitor and all but 2 of those patients had subsequent Tarceva.

Maintenance NSCLC therapy after first-line chemotherapy (Tarceva administered as monotherapy)

The efficacy and safety of Tarceva as maintenance after first-line chemotherapy for NSCLC wasinvestigated in a randomised, double-blind, placebo-controlled trial (BO18192, SATURN). This studywas conducted in 889 patients with locally advanced or metastatic NSCLC who did not progress after4 cycles of platinum-based doublet chemotherapy. Patients were randomised 1:1 to receive Tarceva150 mg or placebo orally once daily until disease progression. The primary endpoint of the studyincluded progression free survival (PFS) in all patients. Baseline demographic and diseasecharacteristics were well balanced between the two treatment arms. Patients with ECOG PS>1,significant hepatic or renal co-morbidities were not included in the study.

In this study, the overall population showed a benefit for the primary PFS end-point (HR= 0.71p< 0.0001) and the secondary OS end-point (HR= 0.81 p=0.0088). However the largest benefit wasobserved in a predefined exploratory analysis in patients with EGFR activating mutations (n= 49)demonstrating a substantial PFS benefit (HR=0.10, 95% CI, 0.04 to 0.25; p<0.0001) and an overallsurvival HR of 0.83 (95% CI, 0.34 to 2.02). 67% of placebo patients in the EGFR mutation positivesubgroup received second or further line treatment with EGFR-TKIs.

The BO25460 (IUNO) study was conducted in 643 patients with advanced NSCLC whose tumors didnot harbor an EGFR-activating mutation (exon 19 deletion or exon 21 L858R mutation) and who hadnot experienced disease progression after four cycles of platinum-based chemotherapy.

The objective of the study was to compare the overall survival of first line maintenance therapy witherlotinib versus erlotinib administered at the time of disease progression. The study did not meet itsprimary endpoint. OS of Tarceva in first line maintenance was not superior to Tarceva as second linetreatment in patients whose tumor did not harbor an EGFR-activating mutation (HR= 1.02, 95% CI,0.85 to 1.22, p=0.82). The secondary endpoint of PFS showed no difference between Tarceva andplacebo in maintenance treatment (HR=0.94, 95 % CI, 0.80 to 1.11; p=0.48).

Based on the data from the BO25460 (IUNO) study, Tarceva use is not recommended for first-linemaintenance treatment in patients without an EGFR activating mutation.

NSCLC treatment after failure of at least one prior chemotherapy regimen (Tarceva administered asmonotherapy)

The efficacy and safety of Tarceva as second/third-line therapy was demonstrated in a randomised,double-blind, placebo-controlled trial (BR.21), in 731 patients with locally advanced or metastatic

NSCLC after failure of at least one chemotherapy regimen. Patients were randomised 2:1 to receive

Tarceva 150 mg or placebo orally once daily. Study endpoints included overall survival,progression-free survival (PFS), response rate, duration of response, time to deterioration of lungcancer-related symptoms (cough, dyspnoea and pain), and safety. The primary endpoint was survival.

Demographic characteristics were well balanced between the two treatment groups. About two-thirdsof the patients were male and approximately one-third had a baseline ECOG performance status (PS)of 2, and 9% had a baseline ECOG PS of 3. Ninety-three percent and 92% of all patients in the

Tarceva and placebo groups, respectively, had received a prior platinum-containing regimen and 36%and 37% of all patients, respectively, had received a prior taxane therapy.

The adjusted hazard ratio (HR) for death in the Tarceva group relative to the placebo group was 0.73(95% CI, 0.60 to 0.87) (p = 0.001). The percent of patients alive at 12 months was 31.2% and 21.5%,for the Tarceva and placebo groups, respectively. The median overall survival was 6.7 months in the

Tarceva group (95% CI, 5.5 to 7.8 months) compared with 4.7 months in the placebo group (95% CI,4.1 to 6.3 months).

The effect on overall survival was explored across different patient subsets. The effect of Tarceva onoverall survival was similar in patients with a baseline performance status (ECOG) of 2-3 (HR = 0.77,95% CI 0.6-1.0) or 0-1 (HR = 0.73, 95% CI 0.6-0.9), male (HR = 0.76, 95% CI 0.6-0.9) or femalepatients (HR = 0.80, 95% CI 0.6-1.1), patients < 65 years of age (HR = 0.75, 95% CI 0.6-0.9) or olderpatients (HR = 0.79, 95% CI 0.6-1.0), patients with one prior regimen (HR = 0.76, 95% CI 0.6-1.0) ormore than one prior regimen (HR = 0.75, 95% CI 0.6-1.0), Caucasian (HR = 0.79, 95% CI 0.6-1.0) or

Asian patients (HR = 0.61, 95% CI 0.4-1.0), patients with adenocarcinoma (HR = 0.71, 95%

CI 0.6-0.9) or squamous cell carcinoma (HR = 0.67, 95% CI 0.5-0.9), but not in patients with otherhistologies (HR 1.04, 95% CI 0.7-1.5), patients with stage IV disease at diagnosis (HR = 0.92, 95%

CI 0.7-1.2) or < stage IV disease at diagnosis (HR = 0.65, 95% CI 0.5-0.8). Patients who neversmoked had a much greater benefit from erlotinib (survival HR = 0.42, 95% CI 0.28-0.64) comparedwith current or ex-smokers (HR = 0.87, 95% CI 0.71-1.05).

In the 45% of patients with known EGFR-expression status, the hazard ratio was 0.68 (95%

CI 0.49-0.94) for patients with EGFR-positive tumours and 0.93 (95% CI 0.63-1.36) for patients with

EGFR-negative tumours (defined by IHC using EGFR pharmDx kit and defining EGFR-negative asless than 10% tumour cells staining). In the remaining 55% of patients with unknown

EGFR-expression status, the hazard ratio was 0.77 (95% CI 0.61-0.98).

The median PFS was 9.7 weeks in the Tarceva group (95% CI, 8.4 to 12.4 weeks) compared with8.0 weeks in the placebo group (95% CI, 7.9 to 8.1 weeks).

The objective response rate by RECIST in the Tarceva group was 8.9% (95% CI, 6.4 to 12.0).

The first 330 patients were centrally assessed (response rate 6.2%); 401 patients were investigator-assessed (response rate 11.2%).

The median duration of response was 34.3 weeks, ranging from 9.7 to 57.6+ weeks. The proportion ofpatients who experienced complete response, partial response or stable disease was 44.0% and 27.5%,respectively, for the Tarceva and placebo groups (p = 0.004).

A survival benefit of Tarceva was also observed in patients who did not achieve an objective tumourresponse (by RECIST). This was evidenced by a hazard ratio for death of 0.82 (95% CI, 0.68 to 0.99)among patients whose best response was stable disease or progressive disease.

Tarceva resulted in symptom benefits by significantly prolonging time to deterioration in cough,dyspnoea and pain, versus placebo.

In a double-blind, randomised phase III study (MO22162, CURRENTS) comparing two doses of

Tarceva (300 mg versus 150 mg) in current smokers (mean of 38 pack years) with locally advanced ormetastatic NSCLC in the second-line setting after failure on chemotherapy, the 300 mg dose of

Tarceva demonstrated no PFS benefit over the recommended dose (7.00 vs 6.86 weeks, respectively).

Secondary efficacy endpoints were all consistent with the primary endpoint and no difference wasdetected for OS between patients treated with erlotinib 300 mg and 150 mg daily (HR 1.03, 95% CI0.80 to 1.32). Safety data were comparable between the 300 mg and 150 mg doses; however, therewas a numerical increase in the incidence of rash, interstitial lung disease and diarrhoea, in patientsreceiving the higher dose of erlotinib. Based on the data from the CURRENTS study, no evidence wasseen for any benefit of a higher erlotinib dose of 300 mg when compared with the recommended doseof 150 mg in active smokers.

Patients in this study were not selected based on EGFR mutation status. See sections 4.2, pct. 4.4, 4.5, and5.2.

Pancreatic cancer (Tarceva administered concurrently with gemcitabine in study PA.3)

The efficacy and safety of Tarceva in combination with gemcitabine as a first-line treatment wasassessed in a randomised, double-blind, placebo-controlled trial in patients with locally advanced,unresectable or metastatic pancreatic cancer. Patients were randomised to receive Tarceva or placeboonce daily on a continuous schedule plus gemcitabine IV (1000 mg/m2, Cycle 1 - Days 1, 8, 15, 22,29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4 week cycle[approved dose and schedule for pancreatic cancer, see the gemcitabine SPC]). Tarceva or placebowas taken orally once daily until disease progression or unacceptable toxicity. The primary endpointwas overall survival.

Baseline demographic and disease characteristics of the patients were similar between the 2 treatmentgroups, 100 mg Tarceva plus gemcitabine or placebo plus gemcitabine, except for a slightly largerproportion of females in the erlotinib/gemcitabine arm compared with the placebo/gemcitabine arm:

Baseline Tarceva Placebo

Females 51% 44%

Baseline ECOG performance status (PS) = 0 31% 32%

Baseline ECOG performance status (PS) = 1 51% 51%

Baseline ECOG performance status (PS) = 2 17% 17%

Metastatic disease at baseline 77% 76%

Survival was evaluated in the intent-to-treat population based on follow-up survival data. Results areshown in the table below (results for the group of metastatic and locally advanced patients are derivedfrom exploratory subgroup analysis).

Tarceva Placebo ∆ CI of P-

Outcome (months) (months) (months) CI of ∆ HR HR value

Overall Population

Median overall survival 6.4 6.0 0.41 -0.54-1.64

Mean overall survival 8.8 7.6 1.16 -0.05-2.34 0.82 0.69-0.98 0.028

Metastatic Population

Median overall survival 5.9 5.1 0.87 -0.26-1.56

Mean overall survival 8.1 6.7 1.43 0.17-2.66 0.80 0.66-0.98 0.029

Locally Advanced Population

Median overall survival 8.5 8.2 0.36 -2.43-2.96

Mean overall survival 10.7 10.5 0.19 -2.43-2.69 0.93 0.65-1.35 0.713

In a post-hoc analysis, patients with favourable clinical status at baseline (low pain intensity, good

QoL and good PS) may derive more benefit from Tarceva. The benefit is mostly driven by thepresence of a low pain intensity score.

In a post-hoc analysis, patients on Tarceva who developed a rash had a longer overall survivalcompared to patients who did not develop rash (median OS 7.2 months vs 5 months, HR:0.61).90% of patients on Tarceva developed rash within the first 44 days. The median time to onset of rashwas 10 days.

The European Medicines Agency has waived the obligation to submit the results of studies with

Tarceva in all subsets of the paediatric population in Non Small Cell Lung Cancer and Pancreaticcancer indications (see section 4.2 for information on paediatric use).

After oral administration, erlotinib peak plasma levels are obtained in approximately 4 hours after oraldosing. A study in normal healthy volunteers provided an estimate of the absolute bioavailability of59%. The exposure after an oral dose may be increased by food.

Erlotinib has a mean apparent volume of distribution of 232 l and distributes into tumour tissue ofhumans. In a study of 4 patients (3 with non-small cell lung cancer [NSCLC], and 1 with laryngealcancer) receiving 150 mg daily oral doses of Tarceva, tumour samples from surgical excisionson Day 9 of treatment revealed tumour concentrations of erlotinib that averaged 1185 ng/g of tissue.

This corresponded to an overall average of 63% (range 5-161%) of the steady state observed peakplasma concentrations. The primary active metabolites were present in tumour at concentrationsaveraging 160 ng/g tissue, which corresponded to an overall average of 113% (range 88-130%) of theobserved steady state peak plasma concentrations. Plasma protein binding is approximately 95%.

Erlotinib binds to serum albumin and alpha-1 acid glycoprotein (AAG).

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and toa lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib.

There are three main metabolic pathways identified: 1) O-demethylation of either side chain or both,followed by oxidation to the carboxylic acids; 2) oxidation of the acetylene moiety followed byhydrolysis to the aryl carboxylic acid; and 3) aromatic hydroxylation of the phenyl-acetylene moiety.

The primary metabolites OSI-420 and OSI-413 of erlotinib produced by O-demethylation of eitherside chain have comparable potency to erlotinib in non-clinical in vitro assays and in vivo tumourmodels. They are present in plasma at levels that are <10% of erlotinib and display similarpharmacokinetics as erlotinib.

Erlotinib is excreted predominantly as metabolites via the faeces (>90%) with renal eliminationaccounting for only a small amount (approximately 9%) of an oral dose. Less than 2% of the orallyadministered dose is excreted as parent substance. A population pharmacokinetic analysis in591 patients receiving single agent Tarceva shows a mean apparent clearance of 4.47 l/hour with amedian half-life of 36.2 hours. Therefore, the time to reach steady state plasma concentration would beexpected to occur in approximately 7-8 days.

Based on population pharmacokinetic analysis, no clinically significant relationship between predictedapparent clearance and patient age, bodyweight, gender and ethnicity were observed. Patient factors,which correlated with erlotinib pharmacokinetics, were serum total bilirubin, AAG and currentsmoking. Increased serum concentrations of total bilirubin and AAG concentrations were associatedwith a reduced erlotinib clearance. The clinical relevance of these differences is unclear. However,smokers had an increased rate of erlotinib clearance. This was confirmed in a pharmacokinetic studyin non-smoking and currently cigarette smoking healthy subjects receiving a single oral dose of150 mg erlotinib. The geometric mean of the Cmax was 1056 ng/mL in the non-smokers and 689 ng/mLin the smokers with a mean ratio for smokers to non-smokers of 65.2% (95% CI: 44.3 to 95.9,p = 0.031). The geometric mean of the AUC0-inf was 18726 ng*h/mL in the non-smokers and 6718ng*h/mL in the smokers with a mean ratio of 35.9% (95% CI: 23.7 to 54.3, p < 0.0001). The geometricmean of the C24h was 288 ng/mL in the non-smokers and 34.8 ng/mL in the smokers with a mean ratioof 12.1% (95% CI: 4.82 to 30.2, p = 0.0001). In the pivotal Phase III NSCLC trial, current smokersachieved erlotinib steady state trough plasma concentration of 0.65 µg/mL (n=16) which wasapproximately 2-fold less than the former smokers or patients who had never smoked (1.28 µg/mL,n=108). This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance. In aphase I dose escalation study in NSCLC patients who were current smokers, pharmacokinetic analysesat steady-state indicated a dose proportional increase in erlotinib exposure when the Tarceva dose wasincreased from 150 mg to the maximum tolerated dose of 300 mg. Steady-state trough plasmaconcentrations at a 300 mg dose in current smokers in this study was 1.22 µg/mL (n=17). Seesections 4.2, pct. 4.4, 4.5 and 5.1.

Based on the results of pharmacokinetic studies, current smokers should be advised to stop smokingwhile taking Tarceva, as plasma concentrations could be reduced otherwise.

Based on population pharmacokinetic analysis, the presence of an opioid appeared to increaseexposure by about 11%.

A second population pharmacokinetic analysis was conducted that incorporated erlotinib data from204 pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis demonstratedthat covariants affecting erlotinib clearance in patients from the pancreatic study were very similar tothose seen in the prior single agent pharmacokinetic analysis. No new covariate effects wereidentified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance.

There have been no specific studies in paediatric patients.

There have been no specific studies in elderly patients.

Erlotinib is primarily cleared by the liver. In patients with solid tumours and with moderately impairedhepatic function (Child-Pugh score 7-9), geometric mean erlotinib AUC0-t and Cmax was 27000ng*h/mL and 805 ng/mL, respectively, as compared to 29300 ng*h/mL and 1090 ng/mL in patientswith adequate hepatic function including patients with primary liver cancer or hepatic metastases.

Although the Cmax was statistically significant lower in moderately hepatic impaired patients, thisdifference is not considered clinically relevant. No data are available regarding the influence of severehepatic dysfunction on the pharmacokinetics of erlotinib. In population pharmacokinetic analysis,increased serum concentrations of total bilirubin were associated with a slower rate of erlotinibclearance.

Erlotinib and its metabolites are not significantly excreted by the kidney, as less than 9% of a singledose is excreted in the urine. In population pharmacokinetic analysis, no clinically significantrelationship was observed between erlotinib clearance and creatinine clearance, but there are no dataavailable for patients with creatinine clearance <15 ml/min.

Chronic dosing effects observed in at least one animal species or study included effects on the cornea(atrophy, ulceration), skin (follicular degeneration and inflammation, redness, and alopecia), ovary(atrophy), liver (liver necrosis), kidney (renal papillary necrosis and tubular dilatation), andgastrointestinal tract (delayed gastric emptying and diarrhoea). Red blood cell parameters weredecreased and white blood cells, primarily neutrophils, were increased. There were treatment-relatedincreases in ALT, AST and bilirubin. These findings were observed at exposures well below clinicallyrelevant exposures.

Based on the mode of action, erlotinib has the potential to be a teratogen. Data from reproductivetoxicology tests in rats and rabbits at doses near the maximum tolerated dose and/or maternally toxicdoses showed reproductive (embryotoxicity in rats, embryo resorption and foetotoxicity in rabbits) anddevelopmental (decrease in pup growth and survival in rats) toxicity, but was not teratogenic and didnot impair fertility. These findings were observed at clinically relevant exposures.

Erlotinib tested negative in conventional genotoxicity studies. Two-year carcinogenicity studies witherlotinib conducted in rats and mice were negative up to exposures exceeding human therapeuticexposure (up to 2-fold and 10-fold higher, respectively, based on Cmax and/or AUC).

A mild phototoxic skin reaction was observed in rats after UV irradiation.

Lactose monohydrate

Cellulose, microcrystalline (E460)

Sodium starch glycolate Type A

Sodium laurilsulfate

Magnesium stearate (E470 b)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Macrogol

Hypromellose (E464)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

PVC blister sealed with aluminium foil containing 30 tablets.

No special requirements for disposal.

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

CHEPLAPHARM Registration GmbH

Weiler Straße 5 E79540 Lörrach

Germany

EU/1/05/311/001

EU/1/05/311/002

EU/1/05/311/003

Date of first authorization: 19 September 2005

Date of latest renewal: 2 July 2010

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

Medicines Agency http://www.ema.europa.eu