Ertinob

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERTINOB (ERTINOB)

Composition:

Active substance: erlotinib;

One film-coated tablet contains erlotinib hydrochloride equivalent to 100 mg or 150 mg of erlotinib;

Excipients: PanExcea MHC 300 G*, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, Opadry II White 85F18422 coating**.

* Composition of PanExcea MHC 300 G: microcrystalline cellulose, crospovidone, hydroxypropylmethylcellulose.

** Composition of Opadry II White 85F18422 coating: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

100 mg tablets: white to almost white, round, biconvex, film-coated tablets, with a break line on both sides;

150 mg tablets: white to almost white, round, biconvex, film-coated tablets, with a break line on both sides.

Pharmacotherapeutic group.

Antineoplastic agents. Protein kinase inhibitors. Erlotinib.

ATC code L01X E03.

Pharmacological Properties.

Pharmacodynamics.

Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (epidermal growth factor receptor type 1 in humans, EGFR, also known as HER1). Erlotinib causes pronounced inhibition of intracellular phosphorylation of EGFR. EGFR is expressed on the surface of both normal and cancer cells. In preclinical models, inhibition of EGFR phosphotyrosine leads to arrest of cell growth and cell death. EGFR-activating mutations may lead to persistent activation of anti-apoptotic and proliferative signaling pathways. The high efficacy of erlotinib in blocking EGFR-mediated signal transduction in tumors with such EGFR mutations is explained by the strong binding of erlotinib to the ATP-binding site [adenosine triphosphate] in the mutated EGFR kinase domain. By blocking downstream signal transmission, cell proliferation is inhibited and cell death is induced via natural apoptosis. In mouse models with enhanced expression of these EGFR-activating mutations, tumor regression has been observed.

Pharmacokinetics.

Absorption. Maximum plasma concentration of erlotinib is reached approximately 4 hours after oral administration. Studies in healthy volunteers have estimated the absolute bioavailability of the drug to be 59%. Exposure after oral administration may be increased by food intake. Distribution. Erlotinib has a mean apparent volume of distribution of 232 L and distributes into human tumor tissues. In a study involving four patients (three with non-small cell lung cancer [NSCLC] and one with laryngeal cancer) who received erlotinib at a dose of 150 mg per day, tumor samples obtained during surgery on day 9 contained erlotinib at a mean concentration of 1185 ng/g of tissue. This corresponds overall to a mean of 63% (range 5–161%) of the maximum plasma concentration at steady state. Primary active metabolites were present in tumor tissue at a mean concentration of 160 ng/g, corresponding to an overall mean of 113% (range 88–130%) of the steady-state maximum stable plasma concentration. Protein binding in plasma is approximately 95%. Erlotinib binds to serum albumin and alpha-1-acid glycoprotein (AAG).

Metabolism. Erlotinib is metabolized in the liver by the cytochrome P450 enzyme system, primarily by CYP3A4 enzymes, and to a lesser extent by CYP1A2. Extrahepatic metabolism of erlotinib occurs via CYP3A4 in the small intestine, and CYP1A1 in the lungs and CYP1B1 in tumor tissue may also be involved in the metabolic clearance of erlotinib. Metabolism proceeds via three pathways: 1) O-demethylation of one or both side chains followed by oxidation to carboxylic acids; 2) oxidation of the acetylenic moiety followed by hydrolysis to arylcarboxylic acids; 3) aromatic hydroxylation of the phenyl-acetylene group. The primary metabolites of erlotinib, OSI-420 and OSI-413, formed by O-demethylation of one of the side chains, have activity comparable to that of erlotinib in preclinical in vitro assays and in vivo tumor models. These metabolites are present in plasma at concentrations less than 10% of the erlotinib concentration, and their pharmacokinetics are similar to those of erlotinib.

Elimination. Erlotinib metabolites are primarily excreted in feces (>90%), with a small amount of the orally administered dose eliminated via the kidneys (approximately 9%). Less than 2% of the orally administered dose is excreted as unchanged drug. Population pharmacokinetic analysis in 591 patients receiving erlotinib as monotherapy showed that the mean apparent clearance was 4.47 L/h, with a median elimination half-life of 36.2 hours. Therefore, the time to reach steady-state plasma concentration is expected to be approximately 7–8 days.

Pharmacokinetics in Special Patient Populations.

Population pharmacokinetic analysis data showed no clinically significant dependence between predicted apparent clearance and patient age, body weight, gender, or ethnicity. Erlotinib pharmacokinetics were influenced by serum total bilirubin concentration, alpha-1-acid glycoprotein (AAG) levels, and current smoking status. Decreased erlotinib clearance was observed with increased total bilirubin and alpha-1-acid glycoprotein concentrations. The clinical significance of this phenomenon is unknown. However, in smokers, accelerated erlotinib clearance was observed, as confirmed in a pharmacokinetic study of a single 150 mg dose of erlotinib administered to non-smokers and current smokers. The geometric mean maximum concentration was 1056 ng/mL in non-smokers and 689 ng/mL in smokers, with a geometric mean ratio of 65.2% (95% CI [confidence interval]: 44.3–95.9; p = 0.031). The geometric mean AUC0–inf was 18726 ng·h/mL in non-smokers and 6718 ng·h/mL in smokers, with a geometric mean ratio of 35.9% (95% CI: 23.7–54.3; p < 0.0001). The geometric mean concentration (24 h) was 288 ng/mL in non-smokers and 34.8 ng/mL in smokers, with a geometric mean ratio of 12.1% (95% CI: 4.82–30.2; p = 0.0001).

In a phase III baseline study in NSCLC patients who were smokers, the minimum steady-state plasma concentration was 0.65 µg/mL (n = 16), which is two times lower than in former smokers or non-smokers (1.28 µg/mL, n = 108). This was accompanied by a 24% increase in plasma clearance of erlotinib.

In a phase I dose-escalation study involving NSCLC patients who smoked during the study, pharmacokinetic analysis at steady state showed dose-proportional increases in erlotinib exposure with dose escalation from 150 mg to the maximum tolerated dose of 300 mg. The steady-state minimum plasma concentration after a 300 mg dose in continuing smokers in this study was 1.22 µg/mL (n = 17).

Based on pharmacokinetic study results, patients who smoke are advised to stop smoking during treatment, as otherwise a reduction in plasma drug concentration may occur.

According to population pharmacokinetic analysis, concomitant use of opioid medications increased erlotinib exposure by approximately 11%.

A second population pharmacokinetic analysis was conducted using data from 204 patients with pancreatic cancer who received erlotinib in combination with gemcitabine. This analysis showed that covariates affecting erlotinib clearance in patients with pancreatic cancer were practically the same as those observed in previous pharmacokinetic analyses under monotherapy conditions. No new covariate effects were identified. Concomitant administration of gemcitabine does not affect erlotinib plasma clearance.

Children. No specific studies have been conducted in pediatric patients.

Elderly patients. No specific studies have been conducted in elderly patients.

Hepatic impairment. In patients with solid tumors and moderate hepatic impairment (7–9 points on the Child–Pugh scale), geometric mean values of AUC0–t and Cmax for erlotinib were 27000 ng·h/mL and 805 ng/mL, respectively, compared to 29300 ng·h/mL and 1090 ng/mL in patients with normal liver function, including those with primary liver cancer or liver metastases. Although Cmax was statistically significantly lower in patients with moderate hepatic impairment, this difference is not considered clinically significant. There are no data on the effect of severe hepatic dysfunction on erlotinib pharmacokinetics. In population pharmacokinetic analysis, increased serum total bilirubin concentration was associated with slower erlotinib elimination.

Renal impairment. Erlotinib and its metabolites are excreted in minimal amounts via the kidneys—less than 9% of a single dose is excreted in urine. In population pharmacokinetic analysis, no clinically significant correlation was observed between erlotinib clearance and creatinine clearance. There are no data for patients with creatinine clearance < 15 mL/min.

Clinical characteristics.

Indications.

Non-small cell lung cancer

First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations.

Ertinob is also indicated for switch maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations who have stable disease following first-line chemotherapy.

Treatment of locally advanced or metastatic non-small cell lung cancer after failure of one or more chemotherapy regimens.

When prescribing Ertinob, factors related to prolonged survival should be considered. No survival benefit or other clinically meaningful treatment effects have been demonstrated in patients whose tumors lack epidermal growth factor receptors (EGFR) as determined by immunohistochemical testing.

Pancreatic cancer

Treatment of metastatic pancreatic cancer in combination with gemcitabine. When prescribing Ertinob, factors related to prolonged survival should be considered.

No survival benefit has been demonstrated in patients with locally advanced pancreatic cancer.

Contraindications.

Hypersensitivity to erlotinib or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Erlotinib and other CYP substrates.

Erlotinib is a potent inhibitor of CYP1A1 and a moderately potent inhibitor of CYP3A4 and CYP2C8, as well as a potent inhibitor of glucuronidation via UGT1A1 in vitro.

The physiological significance of potent CYP1A1 inhibition is unknown due to very limited expression of CYP1A1 in human tissues.

When erlotinib was administered with ciprofloxacin, a moderately potent CYP1A2 inhibitor, erlotinib exposure (AUC) increased by 39%, while maximum concentration (Cmax) did not change significantly. Similarly, AUC and Cmax of active metabolites increased by 60% and 48%, respectively. The clinical significance of this increased exposure has not been established. Therefore, caution is advised when prescribing Ertinob with ciprofloxacin or other potent CYP1A2 inhibitors (e.g., fluvoxamine). If adverse reactions related to erlotinib occur, the dose of the drug may be reduced.

Prior or concomitant administration of Ertinob did not alter the clearance of prototype CYP3A4 substrates midazolam and erythromycin. However, a 24% reduction in oral bioavailability of midazolam was observed. In another clinical study, erlotinib was shown not to affect the pharmacokinetics of the CYP3A4/2C8 substrate paclitaxel when co-administered. Therefore, clinically significant interactions with clearance of other CYP3A4 substrates are unlikely. Inhibition of glucuronidation may lead to interactions with medicinal products that are substrates of UGT1A1 and are eliminated exclusively via this metabolic pathway. Increased serum bilirubin concentrations may occur in patients with low UGT1A1 expression or genetically determined disorders of glucuronidation (e.g., Gilbert’s syndrome); therefore, treatment of these patients requires caution.

Erlotinib is metabolized in the liver primarily by cytochrome P450 enzymes, predominantly CYP3A4, and to a lesser extent CYP1A2. Extrahepatic metabolism involving CYP3A4 in the small intestine, CYP1A1 in the lungs, and CYP1B1 in tumor tissue may also contribute to erlotinib’s metabolic clearance. Potential interactions exist with active substances that are metabolized by these enzymes or are their inducers or inhibitors. Potent inhibitors of CYP3A4 activity reduce erlotinib metabolism and increase its plasma concentration. In a clinical study, co-administration of erlotinib with ketoconazole (200 mg orally twice daily for 5 days)—a potent CYP3A4 inhibitor—resulted in an 86% increase in erlotinib exposure (AUC) and a 69% increase in Cmax. Caution is advised when prescribing Ertinob with potent CYP3A4 inhibitors, including azole antifungals (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, and clarithromycin. If toxicity develops, the dose of Ertinob should be reduced.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly reduce its plasma concentration. In a clinical study, co-administration of erlotinib with rifampicin (600 mg orally once daily for 7 days)—a potent CYP3A4 inducer—resulted in a 69% reduction in median erlotinib AUC. When rifampicin was co-administered with a single 450 mg dose of erlotinib, mean erlotinib exposure (AUC) was 57.5% of that observed after a single 150 mg dose of Ertinob in the absence of rifampicin therapy. Concomitant use of Ertinob and CYP3A4 inducers should be avoided. If a patient requires concomitant treatment with Ertinob and a potent CYP3A4 inducer (such as rifampicin), dose escalation of Ertinob to 300 mg should be considered with careful monitoring of the patient (including renal and hepatic function and serum electrolytes). If well tolerated for more than 2 weeks, the dose of Ertinob may be increased to 450 mg with careful safety monitoring. Reduced erlotinib exposure may occur when co-administered with other CYP3A4 inducers (e.g., phenytoin, carbamazepine, barbiturates, St. John’s wort-containing products). Concomitant use of these agents with erlotinib requires caution. Where possible, alternative medicinal products that are not potent CYP3A4 inducers should be prescribed.

Erlotinib and anticoagulants, coumarin derivatives.

An increased international normalized ratio (INR) and incidence of bleeding, including isolated cases with fatal outcomes, have been reported when erlotinib was used concomitantly with coumarin-derived anticoagulants, including warfarin. In patients receiving coumarin-derived anticoagulants, prothrombin time or INR should be monitored regularly.

Erlotinib and statins.

The risk of statin-induced myopathy, including rare cases of rhabdomyolysis, may be increased when Ertinob is used concomitantly with statins.

Smoking patients

Pharmacokinetic studies in non-smokers and current smokers showed that smoking reduces AUCinf, Cmax, and plasma concentration of erlotinib at 24 hours by 2.8-, 1.5-, and 9-fold, respectively. Therefore, smokers should be advised to quit smoking as early as possible before starting treatment with Ertinob due to reduced erlotinib plasma concentrations with continued smoking. The clinical consequences of reduced erlotinib exposure have not been formally studied, but are likely to be clinically significant.

Erlotinib and P-glycoprotein inhibitors.

Erlotinib is a substrate of the P-glycoprotein drug transporter. Concomitant administration of Ertinob and P-glycoprotein inhibitors (e.g., cyclosporine, verapamil) may alter the distribution and/or elimination of erlotinib. The consequences of such interactions, particularly regarding the central nervous system (e.g., toxic effects), have not been established. Caution is advised in such situations.

Erlotinib and medicinal products affecting pH.

Erlotinib has reduced solubility at pH values above 5. Medicinal products that affect pH in the upper gastrointestinal tract may influence erlotinib solubility and bioavailability. When Ertinob was co-administered with omeprazole, a proton pump inhibitor, erlotinib exposure (AUC) and maximum concentration (Cmax) decreased by 46% and 61%, respectively. Tmax and elimination half-life were unchanged. When erlotinib was co-administered with ranitidine (300 mg), an H2-receptor antagonist, erlotinib exposure (AUC) and Cmax decreased by 33% and 54%, respectively. Increasing the erlotinib dose when co-administered with such agents is unlikely to compensate for the reduced exposure. However, when erlotinib was administered 2 hours before or 10 hours after ranitidine (150 mg twice daily), AUC and Cmax decreased by only 15% and 17%, respectively. The effect of antacids on erlotinib absorption has not been studied, but impaired absorption is possible, potentially leading to reduced plasma levels of erlotinib. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is necessary during Ertinob treatment, antacids should be taken at least 4 hours before or 2 hours after the daily dose of Ertinob. If ranitidine is prescribed, its administration should be staggered relative to Ertinob: the drug should be taken at least 2 hours before or 10 hours after ranitidine.

Erlotinib and gemcitabine.

In a phase Ib study, no significant effect of gemcitabine on erlotinib pharmacokinetics or of erlotinib on gemcitabine pharmacokinetics was observed.

Erlotinib and carboplatin/paclitaxel.

Erlotinib increases platinum concentrations in plasma. In a clinical study, co-administration of erlotinib with carboplatin and paclitaxel resulted in a statistically significant 10.6% increase in AUC0–48 of total platinum, but this was not clinically significant. In clinical practice, other concomitant factors may contribute to increased carboplatin exposure, such as impaired renal function. No significant effect of carboplatin or paclitaxel on erlotinib pharmacokinetics was observed.

Erlotinib and capecitabine.

Capecitabine may cause increased erlotinib concentrations. Following erlotinib administration in combination with capecitabine, statistically significant increases in erlotinib AUC and borderline increases in Cmax were observed compared to values from another study where erlotinib was used as monotherapy. No significant effect of erlotinib on capecitabine pharmacokinetics was observed.

Erlotinib and proteasome inhibitors.

Based on the mechanism of action, proteasome inhibitors—including bortezomib—may affect the activity of epidermal growth factor receptor (EGFR) inhibitors such as erlotinib. Limited clinical data and preclinical study results support this potential interaction, showing proteasome-mediated degradation of EGFR.

Special precautions for use.

Testing for epidermal growth factor receptor mutations.

When considering the use of the medicinal product Ertinob as a first-line or maintenance therapy for locally advanced or metastatic NSCLC, it is important to determine the EGFR mutation status of the patient.

A validated, reliable and sensitive test with a predefined positivity threshold and demonstrated utility for determining EGFR mutation status, using tumour DNA obtained from a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be used in accordance with local medical practice requirements. If a plasma-based cfDNA test is used and the result is negative for activating mutations, a tissue test should be performed, where possible, due to the possibility of false-negative plasma-based test results.

Use in smokers.

Smokers should be advised to stop smoking, as the plasma concentration of erlotinib is reduced in smokers compared to non-smokers. The extent of reduction in erlotinib plasma concentration is likely to be clinically significant (see section "Interaction with other medicinal products and other forms of interaction").

Interstitial lung disease.

Interstitial lung disease (ILD)-like events, including fatal cases, have been reported rarely in patients receiving erlotinib for the treatment of NSCLC, pancreatic cancer or other progressive solid tumours. In the BR.21 pivotal trial in NSCLC, the incidence of ILD (0.8%) was the same in both placebo and erlotinib groups. According to a meta-analysis of randomised controlled clinical trials in NSCLC (excluding phase I trials and single-arm phase II trials due to the absence of control groups), the incidence of ILD-like events was 0.9% in patients receiving erlotinib compared to 0.4% in placebo groups. In the pancreatic cancer trial, the incidence of ILD-like events was 2.5% in the erlotinib plus gemcitabine group compared to 0.4% in the placebo plus gemcitabine group. Specifically, diagnoses reported in patients with suspected ILD included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, alveolitis and lung infiltration. Symptoms appeared from several days to several months after initiation of erlotinib therapy. Contributing factors often included concomitant or prior chemotherapy, prior radiotherapy, underlying parenchymal lung disease, metastatic lung disease or lung infections. A higher incidence of ILD (approximately 5% with a mortality rate of 1.5%) was observed among patients in trials conducted in Japan.

If a patient develops acute onset of new and/or unexplained progressive pulmonary symptoms such as dyspnoea, cough and fever, erlotinib should be discontinued pending diagnostic evaluation. Patients receiving erlotinib and gemcitabine concomitantly should be closely monitored to avoid the development of ILD-like toxicity. If ILD is diagnosed, erlotinib should be discontinued and appropriate treatment initiated if necessary (see section "Undesirable effects").

Diarrhoea, dehydration, electrolyte imbalance and renal failure.

Diarrhoea (including very rare fatal cases) was observed in approximately 50% of patients receiving erlotinib treatment. In cases of severe or moderate diarrhoea, treatment with, for example, loperamide should be initiated. In some cases, dose reduction may be required. In clinical trials, doses were reduced in 50 mg steps. Dose reductions in 25 mg steps have not been studied. Erlotinib treatment should be interrupted and appropriate measures taken to correct dehydration in cases of severe or persistent diarrhoea, nausea, anorexia or vomiting associated with dehydration (see section "Undesirable effects"). Hypokalaemia and renal failure (including fatal cases) have been reported rarely. In some cases, dehydration was due to diarrhoea, vomiting and/or anorexia, while in others, interpretation was complicated by concomitant chemotherapy. In cases of more severe or persistent diarrhoea or cases leading to dehydration, especially in patient groups with predisposing risk factors (concomitant use of other drugs, presence of symptoms or conditions, or other susceptibility factors, including advanced age), treatment with Ertinob should be interrupted and appropriate measures taken, including intensive intravenous rehydration. In patients at risk of dehydration, renal function and serum electrolyte levels, including potassium, should also be monitored.

Hepatitis, hepatic failure.

Cases of drug-induced liver injury (including hepatitis, acute hepatitis and hepatic failure), including cases of hepatic failure (some fatal), have been reported rarely during erlotinib treatment. Contributing factors complicating interpretation include pre-existing liver disease and concomitant use of hepatotoxic medicinal products. Therefore, periodic monitoring of liver function is necessary in these patients. Erlotinib treatment should be interrupted in case of marked abnormalities in liver function (see section "Undesirable effects"). Ertinob is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforation.

Patients taking Ertinob are at increased risk of gastrointestinal perforation, which occurs infrequently (including isolated fatal cases). The risk of gastrointestinal perforation is increased in patients receiving concomitant therapy with anti-angiogenic agents, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or taxane-based chemotherapy, as well as in patients with a history of peptic ulcer or diverticular disease. Erlotinib treatment should be permanently discontinued if gastrointestinal perforation occurs (see section "Undesirable effects").

Bullous and exfoliative skin disorders.

Bullous, blistering and exfoliative skin disorders, including very rare cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, some of which were fatal, have been observed during treatment with Ertinob (see section "Undesirable effects"). Erlotinib treatment should be temporarily withheld or discontinued in the event of bullous, blistering or exfoliative skin disorders. Patients with bullous and exfoliative skin disorders should be evaluated for skin infections and treated according to local recommendations.

Ocular disorders.

Patients presenting with signs and symptoms typical of keratitis, such as acute onset or worsening of eye inflammation, lacrimation, photophobia, blurred vision, eye pain and/or redness, should be referred immediately for ophthalmological evaluation. Erlotinib treatment should be temporarily or permanently discontinued in case of confirmed ulcerative keratitis. The benefit-risk balance of continuing Ertinob treatment should be carefully considered in case of keratitis. Ertinob 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 corneal ulceration. Cases of corneal perforation or ulceration during treatment with Ertinob have been reported very rarely (see section "Undesirable effects").

Interaction with other medicinal products.

Strong inducers of CYP3A4 enzymes may reduce the efficacy of erlotinib, whereas strong inhibitors of CYP3A4 may lead to increased toxicity. Concomitant use of Ertinob with such agents should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Other forms of interaction.

Erlotinib has reduced solubility at pH levels above 5. Medicinal products that alter the pH in the upper gastrointestinal tract (GIT), such as proton pump inhibitors, H2-receptor antagonists and antacids, may affect erlotinib solubility and thus its bioavailability. It is unlikely that increasing the dose of Ertinob when co-administered with these agents can compensate for the reduced exposure. Concomitant use of Ertinob with proton pump inhibitors should be avoided. The consequences of concomitant use of erlotinib with H2-receptor antagonists and antacids are unknown, but reduced bioavailability is possible. Therefore, concomitant use should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). If antacid therapy is necessary, antacids should be taken at least 4 hours before or 2 hours after the daily dose of Ertinob.

Disposal of unused medicine and medicine past its expiry date.
Environmental contamination should be minimised. The medicine should not be disposed of via wastewater or household waste. "Waste collection systems" should be used for disposal if available.

Important information on excipients.
This medicinal product contains less than 1 mmol of sodium (less than 23 mg) per tablet, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

There are insufficient data on the use of erlotinib in pregnant women. Animal studies have demonstrated no evidence of teratogenic effects or delivery abnormalities. However, a negative effect on pregnancy cannot be excluded, as increased embryofetal lethality was observed in animal studies. The potential risk in humans is unknown. Women of childbearing potential should avoid pregnancy and use reliable contraception during treatment with Ertinob and for at least 2 weeks after completion of treatment. Treatment of a pregnant woman should only continue if the expected benefit to the mother outweighs the potential risk to the foetus.

Breastfeeding.

It is unknown whether erlotinib is excreted in human breast milk. Women receiving Ertinob are advised to discontinue breastfeeding.

Fertility.

Animal studies indicate no impairment of fertility. However, an adverse effect on fertility cannot be excluded, as effects on reproductive parameters were observed in animal studies. The potential risk in humans is unknown.

Ability to influence the ability to drive and use machines.

Studies on the influence on the ability to drive or operate machinery have not been conducted; however, the effect of erlotinib is not expected to impair mental function.

Method of Administration and Dosage.

Treatment with the medicinal product Erthinob should be conducted by a physician experienced in anticancer therapy.

Non-small cell lung cancer.

Prior to initiating treatment with Erthinob in patients with advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy, testing for epidermal growth factor receptor (EGFR) mutations is required.

The recommended dose of Erthinob is 150 mg once daily, taken 1 hour before or 2 hours after a meal.

Pancreatic cancer.

The recommended dose of Erthinob is 100 mg once daily, taken 1 hour before or 2 hours after a meal, in combination with gemcitabine (see also the gemcitabine package leaflet for medical use, indication: pancreatic cancer).

If no rash develops during the first 4–8 weeks of treatment, the continuation of therapy with Erthinob should be reconsidered (see section "Pharmacodynamics").

If dose adjustment is required, the dose should be reduced in 50 mg decrements (see section "Special precautions for use"). When co-administering substrates and modulators of CYP3A4, dose adjustment may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment.

Erlotinib is eliminated via hepatic metabolism and excreted in bile. Although erlotinib exposure was approximately similar in patients with moderate hepatic impairment (Child–Pugh score 7–9) compared to those with normal liver function, caution should be exercised when administering Erthinob to patients with hepatic insufficiency. In case of severe adverse reactions, the dose of Erthinob should be reduced or treatment discontinued. The safety and efficacy of erlotinib in patients with severe hepatic impairment [AST/SGOT (aspartate aminotransferase/serum glutamic oxaloacetic transaminase) and ALT/SGPT (alanine aminotransferase/serum glutamic pyruvic transaminase) > 5 × ULN (upper limit of normal)] have not been studied; therefore, Erthinob is not recommended for use in such patients (see section "Pharmacokinetics").

Renal impairment.

The safety and efficacy of Erthinob in patients with renal impairment [serum creatinine concentration 1.5 times above the upper limit of normal (ULN)] have not been studied. Based on pharmacokinetic data, dose adjustment is not recommended in patients with mild to moderate renal impairment (see section "Pharmacokinetics"). Erthinob is not recommended for use in patients with severe renal impairment.

Use in smokers.

Smoking reduces erlotinib exposure by 50–60%. The maximum tolerated dose of erlotinib in patients with non-small cell lung cancer who smoke is 300 mg. The efficacy and long-term safety of doses exceeding the recommended initial dose have not been established in patients who continue to smoke (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacokinetics"). Therefore, patients who continue to smoke are advised to quit, as erlotinib plasma concentrations are lower in smokers compared to non-smokers.

Children.

The safety and efficacy of erlotinib in patients under 18 years of age have not been established. The use of Erthinob in children is not recommended.

Overdose.

Symptoms.

Single oral doses of erlotinib up to 1000 mg in healthy volunteers and up to 1600 mg in cancer patients were well tolerated. Tolerability of multiple daily doses of 200 mg twice daily in healthy volunteers worsened only after several days of administration. According to data from these studies, overdose may result in severe adverse reactions, including diarrhea, rash, and possibly elevated liver transaminase levels.

Treatment.

In case of suspected overdose, treatment should be discontinued and symptomatic therapy initiated.

Adverse reactions.

Brief description of the safety profile.

The safety assessment of erlotinib is based on data from more than 1500 patients who received at least one dose of 150 mg erlotinib as monotherapy, and more than 300 patients who received erlotinib 100 or 150 mg in combination with gemcitabine.

Non-small cell lung cancer (erlotinib as monotherapy).

First-line treatment of patients with EGFR mutations.

In the open-label, randomized phase III trial ML20650 involving 154 patients, the safety of erlotinib for first-line treatment of patients with NSCLC harboring activating EGFR mutations was evaluated in 75 patients.

The most common adverse reactions in patients receiving erlotinib in study ML20650 were rash and diarrhea, mostly of grade 1/2 severity, which were manageable with treatment. Full information on the severity and frequency of rash and diarrhea across all clinical studies is provided in the section «Description of selected adverse reactions» below.

Maintenance treatment.

In two other double-blind, randomized, placebo-controlled phase III trials, BO18192 (SATURN) and BO25460 (IUNO), erlotinib was administered as maintenance therapy following first-line chemotherapy. These trials included a total of 1532 patients with advanced, recurrent, or metastatic NSCLC after standard platinum-based first-line chemotherapy.

The most common adverse reactions in patients receiving erlotinib in studies BO18192 and BO25460 were rash and diarrhea.

Second- and subsequent-line treatment.

In the randomized, double-blind trial BR.21, in which erlotinib was used as second-line therapy, the most common adverse reactions were rash and diarrhea. The majority of adverse reactions were of grade 1/2 severity and resolved without intervention. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.

Pancreatic cancer (erlotinib in combination with gemcitabine).

The most common adverse reactions in the main study PA.3 among patients with pancreatic cancer who received erlotinib 100 mg + gemcitabine were fatigue, rash, and diarrhea. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively.

Summary of adverse reactions in tabular form.

Table 1 summarizes adverse reactions reported during clinical trials and post-marketing surveillance with erlotinib used either as monotherapy or in combination with chemotherapy. Adverse reactions are categorized by organ systems according to MedDRA [Medical Dictionary for Regulatory Activities]. Frequency of adverse reactions is defined using the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 1. Adverse reactions based on clinical trials and post-marketing surveillance.

Infections and infestations
Very common	infection*
Metabolism and nutrition disorders
Very common	anorexia, weight decreased
Psychiatric disorders
Very common	depression
Nervous system disorders
Very common	neuropathy, headache
Eye disorders
Very common	dry keratoconjunctivitis
Common	keratitis, conjunctivitis
Uncommon	eyelash changes*
Very rare	corneal perforations, corneal ulcers, uveitis
Respiratory, thoracic and mediastinal disorders
Very common	dyspnea, cough
Common	epistaxis
Uncommon	interstitial lung disease*
Gastrointestinal disorders
Very common	diarrhea*, nausea, vomiting, stomatitis, abdominal pain, dyspepsia, flatulence
Common	gastrointestinal hemorrhage*
Uncommon	gastrointestinal perforations*
Rare	pneumatosis intestinalis
Hepatobiliary disorders
Very common	liver function test abnormalities*
Rare	hepatic failure*, hepatitis
Not known	acute hepatitis
Skin and subcutaneous tissue disorders
Very common	rash*, pruritus
Common	alopecia, dry skin, paronychia, folliculitis, acne/acneiform dermatitis, skin fissures
Uncommon	hirsutism, eyebrow changes, nail fragility and loosening, mild skin reactions such as hyperpigmentation
Rare	palmoplantar erythrodysesthesia syndrome
Very rare	Stevens-Johnson syndrome/toxic epidermal necrolysis*
Renal and urinary disorders
Common	renal failure
Uncommon	nephritis, proteinuria
General disorders and administration site conditions
Very common	fatigue, pyrexia, chills

*See section "Description of selected adverse reactions" below.

Description of selected adverse reactions.

Skin rash.

Rash includes acneiform dermatitis. Overall, rash manifests as mild or moderate erythematous and papulopustular rash, which may occur or worsen in areas exposed to sunlight. Patients exposed to sunlight may be advised to wear protective clothing and/or use sunscreen (e.g., mineral-based sunscreen).

Diarrhea.

Diarrhea may lead to dehydration, hypokalemia, and renal failure. Fatal cases have been reported (see section "Special precautions for use").

Table 2. Frequency and severity of rash and diarrhea observed in clinical studies.

Study	Indication	Rash (%)					Diarrhea (%)
		Severity Grade			Actions Taken		Severity Grade			Actions Taken
		All grades	3	4	Discontinuation of use	Dose modification	All grades	3	4	Discontinuation of use	Dose modification
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 cancer	-	5		1	2	-	5		1	2

Infection.

These may be severe infections with or without neutropenia, including pneumonia, sepsis, and cellulitis.

Eyelash changes.

Changes include eyelash growth, excessive growth, and thickening of eyelashes.

Interstitial lung disease (ILD).

ILD includes fatal cases in patients receiving erlotinib for the treatment of NSCLC or other progressive solid tumors. A higher incidence has been observed in patients in Japan (see section "Special precautions for use").

Gastrointestinal bleeding.

Gastrointestinal bleeding includes fatal outcomes (see section "Special precautions for use"). In clinical studies, some cases were associated with concomitant use of warfarin, and others with concomitant use of NSAIDs (see section "Interaction with other medicinal products and other forms of interaction"). Gastrointestinal perforations also include fatal outcomes (see section "Special precautions for use").

Liver function abnormalities.

Abnormalities include increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. Cases were mostly mild or moderate in severity, transient, or associated with liver metastases.

Hepatic failure.

Includes fatal cases. Risk factors include pre-existing liver disease or concomitant use of hepatotoxic medicinal products (see section "Special precautions for use").

Stevens-Johnson syndrome / toxic epidermal necrolysis.

Includes fatal cases (see section "Special precautions for use").

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

15 tablets in a blister pack. 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Nobel Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eskisehir Road No. 299, 81100 Duzce, Turkey