4.1. Therapeutic indications

Non-Small Cell Lung Cancer (NSCLC):

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

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

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

When prescribing Erlotinib Amarox, factors associated with prolonged survival should be taken into account. No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with Epidermal Growth Factor Receptor (EGFR)-IHC negative tumours (see section 5.1).

Pancreatic cancer:

Erlotinib in combination with gemcitabine is indicated for the treatment of patients with metastatic pancreatic cancer.

When prescribing Erlotinib, 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.

4.2. Posology and method of administration

Erlotinib 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 section 4.1).

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

Patients with pancreatic cancer

The recommended daily dose of Erlotinib is 100 mg taken at least one hour before or two hours after the ingestion of food, in combination with gemcitabine (see the summary of product characteristics of gemcitabine for the pancreatic cancer indication). In patients who do not develop rash within the first 4 – 8 weeks of treatment, further Erlotinib 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). Erlotinib 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).

Hepatic impairment

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

Renal impairment

The safety and efficacy of erlotinib has not been studied in patients with renal impairment (serum creatinine concentration >1.5 times the upper normal limit). Based on pharmacokinetic data no dose adjustments appear necessary in patients with mild or moderate renal impairment (see section 5.2). Use of Erlotinib in patients with severe renal impairment is not recommended.

Paediatric population

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

Smokers

Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerated dose of Erlotinib in NSCLC patients who currently smoke cigarettes was 300 mg. The 300 mg dose did not show improved efficacy in second line treatment after failure of chemotherapy compared to the recommended 150 mg dose in patients who continue to smoke cigarettes. 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 and diarrhoea, in patients receiving the higher dose of erlotinib. Current smokers should be advised to stop smoking (see sections 4.4, 4.5, 5.1 and 5.2).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Assessment of EGFR mutation status

When considering the use of Erlotinib as a first line or maintenance treatment for locally advanced or metastatic 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 and demonstrated utility for the determination of EGFR mutation status, using either tumor DNA derived from a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be performed according to local medical practice. If a plasma-based cfDNA test is used and the result is negative for activating mutations, perform a tissue 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 smokers as 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 reported uncommonly in patients receiving erlotinib for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was the same in both the placebo and erlotinib groups. In a meta-analysis of NSCLC randomised controlled clinical trials (excluding phase I and single-arm phase II studies due to lack of control groups), the incidence of ILD-like events was 0.9% on erlotinib compared to 0.4% in patients in the control arms. In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2.5% in the erlotinib plus gemcitabine group versus 0.4% in the placebo plus gemcitabine treated group. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days to several months after initiating erlotinib therapy. Confounding or contributing factors such as concomitant 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 such as dyspnoea, cough and fever, Erlotinib therapy should be interrupted pending diagnostic evaluation. Patients treated concurrently with erlotinib and gemcitabine should be monitored carefully for the possibility to develop ILD-like toxicity. If ILD is diagnosed, Erlotinib should be discontinued and appropriate 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% of patients on erlotinib and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases 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 persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, Erlotinib therapy should be interrupted, and appropriate measures should be taken to treat the dehydration (see section 4.8). There have been rare reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (especially concomitant chemotherapy and other medications, symptoms or diseases or other predisposing conditions including advanced age), Erlotinib therapy should be interrupted, and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.

Hepatotoxicity

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

Gastrointestinal perforation

Patients receiving Erlotinib are at increased risk of developing gastrointestinal perforation, which was observed uncommonly (including some cases with a fatal outcome). Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Erlotinib should be permanently 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 cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal (see section 4.8). Erlotinib treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disorders should 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: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with Erlotinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Erlotinib should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration. Very rare cases of corneal perforation or ulceration have been reported during use of erlotinib (see section 4.8).

Interactions with other medicinal products

Potent inducers of CYP3A4 may reduce the efficacy of erlotinib whereas potent inhibitors of CYP3A4 may 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 the pH 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 Erlotinib when co-administered with such agents is not likely to compensate for the loss of exposure. Combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib 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). If the use of antacids is considered necessary during treatment with Erlotinib Amarox, they should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib Amarox.

Excipients with known effect

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 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 essentially 'sodium -free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 well as a strong inhibitor of glucuronidation by UGT1A1 in vitro.

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

When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure [AUC] increased significantly by 39%, while no statistically significant change in Cmax was found. 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 be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.

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

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

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a 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. Potential interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally twice 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), protease inhibitors, 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 erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% decrease in the median erlotinib AUC. Co-administration of rifampicin with a single 450 mg dose of Erlotinib resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg Erlotinib dose in the absence of rifampicin treatment. Co-administration of Erlotinib with CYP3A4 inducers should therefore be avoided. For patients who require concomitant treatment with Erlotinib and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while their safety (including renal and liver functions and serum electrolytes) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Reduced exposure 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 combined with erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be considered when 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 in patients receiving erlotinib. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.

Erlotinib and statins

The combination of erlotinib 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 erlotinib in smokers as compared to non-smokers. Therefore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with Erlotinib, as plasma erlotinib concentrations are reduced otherwise. Based on the data from the CURRENTS study, no evidence was seen for any benefit of a higher erlotinib dose of 300 mg when compared with the recommended dose of 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 and diarrhoea, in patients receiving the higher dose of erlotinib (see sections 4.2, 4.4, 5.1 and 5.2).

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate for the P-glycoprotein active substance transporter. Concomitant administration of inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or altered elimination of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not been established. 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 the pH of the upper Gastro-Intestinal (GI) tract may alter the solubility of erlotinib and hence its bioavailability. 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 Erlotinib with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [Cmax] by 33% and 54%, respectively. Increasing the dose of Erlotinib when co- administered with such agents is not likely to compensate for this loss of exposure. However, when Erlotinib 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 but absorption may be impaired, leading to lower plasma levels. In summary, the combination of erlotinib with proton pump inhibitors should be avoided. If the use of antacids is considered necessary during treatment with Erlotinib, they should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib. If the use of ranitidine is considered, it should be used in a staggered manner; i.e. Erlotinib must 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 of erlotinib 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 with carboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10.6%. Although statistically significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice, there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.

Erlotinib and Capecitabine

Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination with capecitabine, 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 single agent. 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 to influence the effect of EGFR inhibitors including erlotinib. Such influence is supported by limited clinical data and preclinical studies showing EGFR degradation through the proteasome.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Women of childbearing potential

Women of childbearing potential must be advised to avoid pregnancy while on Erlotinib. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus.

Breast-feeding

It is not known whether erlotinib is excreted in human milk. No studies have been conducted to assess the impact of Erlotinib on milk production or its presence in breast milk. Asthe potential for harm to the nursing infant, mothers should be advised against breast-feeding while receiving Erlotinib and for at least 2 weeks after the final dose.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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

The incidence of adverse drug reactions (ADRs) from clinical trials reported with erlotinib alone or in combination with chemotherapy are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 1. The listed ADRs were those reported in at least 10% (in the erlotinib group) of patients and occurred more frequently (≥3%) in patients treated with erlotinib than in the comparator arm. Other ADRs including those from other studies are summarized in Table 2.

Adverse drug reactions from clinical trials (Table 1) and other ADRs (Table 2) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based 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 be estimated from the available data).

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

Non-small cell lung cancer (erlotinib 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 erlotinib for first-line treatment of NSCLC patients with EGFR activating mutations was assessed in 75 patients; no new safety signals were observed in these patients.

The most frequent ADRs seen in patients treated with erlotinib in study ML20650 were rash and diarrhoea (any Grade 80% and 57%, respectively), most were Grade 1/2 in severity and manageable without intervention. Grade 3 rash and diarrhoea occurred in 9% and 4% of patients, respectively. No Grade 4 rash or diarrhoea was observed. Both rash and diarrhoea resulted in discontinuation of erlotinib in 1% of patients. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 11% and 7% of patients, respectively.

Maintenance treatment

In two other double-blind, randomised, placebo-controlled Phase III studies BO18192 (SATURN) and BO25460 (IUNO); Erlotinib was administered as maintenance after first-line chemotherapy. These studies were conducted in a total of 1532 patients with advanced, recurrent or metastatic NSCLC following first-line standard platinum-based chemotherapy, no new safety signals were identified.

The most frequent ADRs seen in patients treated with erlotinib in studies BO18192 and BO25460 were rash (BO18192: all grades 49.2%, grade 3: 6.0%; BO25460: all grades 39.4%, grade 3: 5.0%) and diarrhoea (BO18192: all grades 20.3%, grade 3: 1.8%; BO25460: all grades 24.2%, grade 3: 2.5%). No Grade 4 rash or diarrhoea was observed in either study. Rash and diarrhoea resulted in discontinuation of erlotinib in 1% and <1% of patients, respectively, in study BO18192, while no patients discontinued for rash or diarrhoea in BO25460. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 8.3% and 3% of patients, respectively, in study BO18192 and 5.6% and 2.8% of patients, respectively, in study BO25460.

Second and Further Line Treatment

In a randomised double-blind study (BR.21; erlotinib administered as second line therapy), rash (75%) and diarrhoea (54%) were the most commonly reported adverse drug reactions (ADRs). Most were Grade 1/2 in severity and manageable without intervention. Grade 3/4 rash and diarrhoea occurred in 9% and 6%, respectively in erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reduction for rash and diarrhoea was needed in 6% and 1% of patients, respectively. In study BR.21, the median time to onset of rash was 8 days, and the median time to onset of diarrhoea was 12 days.

In general, rash manifests as a mild or moderate erythematous and papulopustular rash, which may occur or worsen in sun exposed areas. For patients who are exposed to sun, protective clothing, and/or use of sun-screen (e.g. mineral-containing) may be advisable.

Pancreatic cancer (Erlotinib administered concurrently with gemcitabine)

The most common adverse reactions in pivotal study PA.3 in pancreatic cancer patients receiving erlotinib 100 mg plus gemcitabine were fatigue, rash and diarrhoea. In the erlotinib plus gemcitabine arm, Grade 3/4 rash and diarrhoea were each reported in 5% of patients. The median time to onset of rash and diarrhoea was 10 days and 15 days, respectively. Rash and diarrhoea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving erlotinib plus gemcitabine.

Table 1: ADRs occuring in ≥ 10% of patients in BR.21 (treated with erlotinib) and PA.3 (treated with erlotinib plus gemcitabine) studies and ADRs occurring more frequently (≥3%) than placebo in BR.21 (treated with erlotinib) and PA.3 (treated with erlotinib plus gemcitabine) studies

Erlotinib (BR.21)

N = 485

Erlotinib (PA.3)

N = 259

Frequency category of highest incidence

NCI-CTC Grade

Any Grade

3

4

Any

Grade

3

4

MedDRA Preferred Term

%

%

%

%

%

%

Infections and infestations

Infection*

24

4

0

31

3

<1

very common

Metabolism and nutrition disorders

Anorexia

Weight decreased

52

-

8

-

1

-

-

39

-

2

-

0

very common

very common

Eye disorders

Keratoconjunctivitis sicca

Conjunctivitis

12

12

0

<1

0

0

-

-

-

-

-

-

very common

very common

Psychiatric disorders

Depression

-

-

-

19

2

0

very common

Nervous system disorders

Neuropathy

Headache

-

-

-

-

-

-

13

15

1

<1

<1

0

very common

very common

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cough

41

33

17

4

11

0

-

16

-

0

-

0

very common

very common

Gastrointestinal disorders

Diarrhoea**

Nausea

Vomiting

Stomatitis

Abdominal pain

Dyspepsia

Flatulence

54

33

23

17

11

-

-

6

3

2

<1

2

-

-

<1

0

<1

0

<1

-

-

48

-

-

22

-

17

13

5

-

-

<1

-

<1

0

<1

-

-

0

-

0

0

very common

very common

very common

very common

very common

very common

very common

Skin and subcutaneous tissue disorders

Rash***

Pruritus

Dry skin

Alopecia

75

13

12

-

8

<1

0

-

<1

0

0

-

69

-

-

14

5

-

-

0

0

-

-

0

very common

very common

very common

very common

General disorders and administration site conditions

Fatigue

Pyrexia

Rigors

52

-

-

14

-

-

4

-

-

73

36

12

14

3

0

2

0

0

very common

very common

very common

* Severe infections, with or without neutropenia, have included pneumonia, sepsis, and cellulitis.

** Can lead to dehydration, hypokalemia and renal failure.

*** Rash included dermatitis acneiform.

- corresponds to percentage below threshold.

Table 2: Summary of ADRs per frequency category:

Body System

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 known8

Eye disorders

-Keratitis

-Conjunctivitis1

-Eyelash changes 2

-Corneal perforations

-Corneal ulcerations

-Uveitis

Respiratory, thoracic and mediastinal disorders

-Epistaxis

- Interstitial lung disease (ILD)3

Gastro- intestinal disorders

-Diarrhoea7

-Gastro- intestinal bleeding4, 7

-Gastro- intestinal perforations7

- Pneumatosis intestinalis

Hepatobiliary disorders

-Liver function test abnormalities5

-Hepatic failure6

-Hepatitis

-Acute hepatitis

Skin and subcutaneous tissue disorders

-Rash

-Alopecia

-Dry skin1

-Paronychia

-Folliculitis

-Acne/ Dermatitis acneiform

-Skin fissures

-Hirsutism

-Eyebrow changes

-Brittle and Loose nails

-Mild skin reactions such as hyperpigmentation

-Palmar plantar erythrodys

- aesthesia syndrome

-Stevens-Johnson syndrome/Toxic epidermal necrolysis7

Renal and urinary disorders

-Renal insufficiency1

-Nephritis1

-Proteinuria1

1In clinical study PA.3.

2Including in-growing eyelashes, excessive growth and thickening of the eyelashes.

3Including fatalities, in patients receiving erlotinib for treatment of NSCLC or other advanced solid tumours (see section 4.4). A higher incidence has been observed in patients in Japan (see section 4.4).

4In clinical studies, some cases have been associated with concomitant warfarin administration and some with concomitant NSAID administration (see section 4.5).

5Including increased alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin. These were very common in clinical study PA.3 and common in clinical study BR.21. Cases were mainly mild to moderate in severity, transient in nature or associated with liver metastases.

6Including fatalities. Risk factors may include pre-existing liver disease or concomitant hepatotoxic medications (see section 4.4).

7Including fatalities (see section 4.4).

8Cannot be estimated from the available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

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

Management

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