Tarceva 25 mg, 100 mg, and 150 mg film-coated tablets

Tarceva 25mg

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

Excipients: Each film-coated tablet contains 27.43 mg Lactose monohydrate.

Tarceva 100mg

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

Excipients: Each film-coated tablet contains 69.21 mg Lactose monohydrate.

Tarceva 150mg

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

Excipients: Each film-coated tablet contains 103.82 mg Lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet.

White to yellowish, round, biconvex tablets with 'Tarceva 25' and logo printed in brownish yellow on one side.

White to yellowish, round, biconvex tablets with 'Tarceva 100' and logo printed in grey on one side.

White to yellowish, round, biconvex tablets with 'Tarceva 150' and logo printed in brown 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 as monotherapy for maintenance treatment in patients with locally advanced or metastatic NSCLC with stable disease after 4 cycles of standard platinum-based first-line chemotherapy.

Tarceva is also indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

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 in patients 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 metastatic pancreatic 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.

Non-small cell lung cancer:

EGFR mutation testing should be performed prior to initiation of Tarceva therapy in chemo-naïve patients with advanced or metastatic NSCLC.

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

Pancreatic cancer:

The recommended daily dose of Tarceva 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 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).

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 Tarceva to patients with hepatic impairment. Dose reduction or interruption of Tarceva 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 Tarceva 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 Tarceva in patients with severe renal impairment is not recommended.

Paediatric use: The safety and efficacy of erlotinib has not been studied in patients under 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 tolerated dose of Tarceva in NSCLC patients who currently smoke cigarettes was 300 mg. Efficacy and long term safety of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes (see sections 4.5 and 5.2). Therefore, current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced.

Hypersensitivity to erlotinib or to any of the excipients.

Assessment of EGFR mutation status:

When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.

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).

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 section 4.5).

Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly 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, the incidence of ILD (0.8 %) was the same in both the placebo and Tarceva groups. In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2.5 % in the Tarceva plus gemcitabine group versus 0.4 % in the placebo plus gemcitabine treated group. The overall incidence in Tarceva-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) is approximately 0.6 % compared to 0.2 % in patients on placebo. 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 Tarceva 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.

In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, Tarceva therapy should be interrupted pending diagnostic eva luation. Patients treated concurrently with erlotinib and gemcitabine should be monitored carefully for the possibility to develop ILD-like toxicity. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment initiated as necessary (see section 4.8).

Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50 % of patients on Tarceva 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, Tarceva 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 (concomitant medications, symptoms or diseases or other predisposing conditions including advanced age), Tarceva 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.

Rare cases of hepatic failure (including fatalities) have been reported during use of Tarceva. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. Tarceva dosing should be interrupted if changes in liver function are severe (see section 4.8). Tarceva is not recommended for use in patients with severe hepatic dysfunction.

Patients receiving Tarceva 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. Tarceva should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).

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). Tarceva treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

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 Tarceva should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Tarceva 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 Tarceva (see section 4.8).

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 Tarceva 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 Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva.

The tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Interaction studies have only been performed in adults.

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 C_max was found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and C_max, 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 Tarceva 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 C_max). 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 Tarceva resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg Tarceva dose in the absence of rifampicin treatment. Co-administration of Tarceva with CYP3A4 inducers should therefore be avoided. For patients who require concomitant treatment with Tarceva 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.

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 Tarceva. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.

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

Results of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced AUC_inf, C_max and plasma concentration at 24 hours, respectively, after administration of Tarceva in smokers as compared to non-smokers (see section 5.2). Therefore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with Tarceva, as plasma erlotinib concentrations are reduced otherwise. The clinical effect of the decreased exposure has not been formally assessed but it is likely to be clinically significant.

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 has not been established. Caution should be exercised in such situations.

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 [C_max] by 46 % and 61 %, respectively. There was no change to T_max or half-life. Concomitant administration of Tarceva with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [C_max] 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 [C_max] decreased only by 15% and 17%, respectively. The effect of antacids on the absorption of erlotinib have 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 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. Tarceva must be taken at least 2 hours before or 10 hours after ranitidine dosing.

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 increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with carboplatin and paclitaxel led to an increase of total platinum AUC_0-48 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.

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 C_max 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.

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 can not 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 must be advised to avoid pregnancy while on Tarceva. 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.

Breastfeeding

It is not known whether erlotinib is excreted in human milk. Because of the potential harm to the infant, mothers should be advised against breast-feeding while receiving Tarceva.

Fertility

Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility can not be excluded as animal studies have shown effects on reproductive parameters (see section 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; however erlotinib is not associated with impairment of mental ability.

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

In a randomized double-blind study (BR.21; Tarceva 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 Tarceva-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.

Adverse reactions occurring more frequently (3 %) in Tarceva-treated patients than in the placebo group in the pivotal study BR.21, and in at least 10 % of patients in the Tarceva group, are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 1.

The following terms are used to rank the undesirable effects by frequency: very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1000); very rare (<1/10,000) including isolated reports.

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

Table 1: Very common ADRs in study BR.21

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