Focleros®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOKLEROS®

Composition:

Active substance: erlotinib;

One film-coated tablet contains erlotinib 100 mg or 150 mg (as erlotinib hydrochloride);

Excipients: lactose monohydrate; microcrystalline cellulose and anhydrous calcium hydrogen phosphate; sodium starch glycolate; colloidal anhydrous silicon dioxide; microcrystalline cellulose; sodium lauryl sulfate; magnesium stearate;

Film coating: hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), macrogol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

100 mg tablets: white, round, biconvex film-coated tablets with a break line on both sides, marked with "E90B" on one side and "100" on the other;

150 mg tablets: white, round, biconvex film-coated tablets with a break line on both sides, marked with "E90B" on one side and "150" on the other.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Epidermal growth factor receptor tyrosine kinase inhibitors. Erlotinib.

ATC code L01EB02.

Pharmacological Properties.

Pharmacodynamics.

Erlotinib is an inhibitor of tyrosine kinase 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/or cell death. EGFR mutations may lead to constitutive activation of anti-apoptotic and proliferative signaling pathways. The high efficacy of erlotinib in blocking EGFR-mediated signal transduction in such EGFR mutation-positive tumors is explained by strong binding of erlotinib to the adenosine triphosphate (ATP) binding site within the mutated kinase domain of EGFR. By blocking downstream signal transduction, cell proliferation is arrested 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 tissue. In a study involving 4 patients (3 with non-small cell lung cancer [NSCLC] and 1 with laryngeal cancer) who received erlotinib at a dose of 150 mg daily, tumor samples obtained during surgery on day 9 of treatment contained erlotinib in tissue at a mean concentration of 1185 ng/g. This corresponds to an overall 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 maximum plasma concentration at steady state. Plasma protein binding 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; CYP1A1 in the lungs and CYP1B1 in tumor tissue may also be involved in erlotinib metabolism. 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 erlotinib in preclinical in vitro assays and in vivo tumor models. These metabolites are present in plasma at concentrations less than 10% of erlotinib concentrations, and their pharmacokinetic profile is similar to that of erlotinib.

Elimination. Erlotinib metabolites are predominantly excreted in feces (>90%), with a small portion of the orally administered dose excreted via 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 a mean apparent clearance of 4.47 L/h and a median elimination half-life of 36.2 hours. Therefore, steady-state plasma concentration is expected to be reached in approximately 7–8 days.

Pharmacokinetics in special patient populations. Population pharmacokinetic analysis revealed no clinically significant dependence between predicted apparent clearance and patient age, body weight, gender, or ethnicity. Erlotinib pharmacokinetics correlated with serum total bilirubin levels, alpha-1-acid glycoprotein (AAG) levels, and current smoking status. Increased serum total bilirubin and AAG levels were associated with reduced erlotinib clearance. The clinical significance of this observation is unknown. However, accelerated erlotinib clearance has been observed in smokers, confirmed in a pharmacokinetic study administering a single 150 mg dose of erlotinib to nonsmokers and current smokers. The geometric mean maximum concentration (Cmax) was 1056 ng/mL in nonsmokers and 689 ng/mL in smokers, with a mean ratio of 65.2% (95% confidence interval [CI]: 44.3–95.9; p = 0.031). The geometric mean AUC0–inf was 18726 ng·h/mL in nonsmokers and 6718 ng·h/mL in smokers, with a mean ratio of 35.9% (95% CI: 23.7–54.3; p < 0.0001). The geometric mean 24-hour concentration was 288 ng/mL in nonsmokers and 34.8 ng/mL in smokers, with a mean ratio of 12.1% (95% CI: 4.82–30.2; p = 0.0001). In a phase III pivotal study in current smokers with non-small cell lung cancer, the minimum steady-state plasma concentration was 0.65 µg/mL (n = 16), which is two-fold lower than in former smokers/nonsmokers (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 in NSCLC patients who smoked during the study, steady-state pharmacokinetic analysis showed dose-proportional increases in erlotinib exposure when the dose was increased 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). See also sections «Dosage and administration», «Special warnings and precautions for use», «Interaction with other medicinal products and other forms of interaction».

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

According to population pharmacokinetic analysis, concomitant use of opioids 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 pancreatic cancer patients were practically the same as those observed in previous monotherapy pharmacokinetic analyses. No new covariate effects were identified. Concomitant administration of gemcitabine does not affect the plasma clearance of erlotinib.

Children. Specific studies in pediatric patients have not been conducted.

Elderly patients. Specific studies in elderly patients have not been conducted.

Hepatic impairment. Erlotinib is primarily eliminated via the liver. In patients with solid tumors and moderate hepatic impairment (Child-Pugh score of 7–9 points), 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 urine in minimal amounts—less than 9% of a single dose. In population pharmacokinetic analysis, no clinically significant correlation was observed between erlotinib clearance and creatinine clearance. There are no data in patients with creatinine clearance < 15 mL/min.

Clinical characteristics.

Indications.

Non-small cell lung cancer (NSCLC).

Use as first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations.

The medicinal product Focleros® 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.

The medicinal product Focleros® is also indicated for the treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. In patients with tumors lacking EGFR-activating mutations, Focleros® is indicated when other treatment options are not suitable.

When prescribing Focleros®, factors related to prolonged survival should be considered. No survival benefit or other clinically meaningful treatment effects have been demonstrated in patients with tumors lacking epidermal growth factor receptor (EGFR) as determined by immunohistochemical analysis.

Pancreatic cancer.

Use for the treatment of metastatic pancreatic cancer in combination with gemcitabine.

When prescribing Focleros®, 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 of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only 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 potent inhibitor of UGT1A1 glucuronidation in vitro.

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

When erlotinib was co-administered with ciprofloxacin, a moderate inhibitor of CYP1A2, erlotinib exposure (AUC) increased significantly by 39%, while maximum concentration (Cmax) did not change statistically significantly. Similarly, AUC and Cmax of the active metabolite increased by 60% and 48%, respectively. The clinical significance of this increased exposure has not been established. Therefore, caution is required when prescribing erlotinib with ciprofloxacin or 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 erlotinib did not alter the clearance of prototypical CYP3A4 substrates midazolam and erythromycin. However, a reduction in oral bioavailability of midazolam by up to 24% 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, caution is required in treating such patients.

In humans, erlotinib is metabolized in the liver primarily by cytochrome P450 enzymes, mainly 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 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, concomitant administration of erlotinib with ketoconazole (200 mg orally twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase in erlotinib exposure (by 86% in AUC and by 69% in Cmax). Caution is required when prescribing erlotinib with potent CYP3A4 inhibitors, including azole antifungal agents (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, and clarithromycin. If toxicity develops, the erlotinib dose should be reduced.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly reduce its plasma concentration. In a clinical study, concomitant administration of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% reduction in median erlotinib AUC. When erlotinib 450 mg single dose was co-administered with rifampicin, the mean erlotinib exposure (AUC) was 57.5% of that observed after a single 150 mg erlotinib dose without rifampicin therapy. Concomitant use of erlotinib and CYP3A4 inducers should be avoided. If a patient requires concomitant treatment with erlotinib and a potent CYP3A4 inducer (such as rifampicin), consideration should be given to increasing the erlotinib dose to 300 mg with careful monitoring of patient safety (including renal and hepatic function and serum electrolyte levels). If well tolerated for more than 2 weeks, the erlotinib dose may be increased to 450 mg with careful safety monitoring. Reduced erlotinib exposure is possible when co-administered with other CYP3A4 inducers (phenytoin, carbamazepine, barbiturates, St. John’s wort-containing products). Concomitant use of these agents with erlotinib requires caution. Alternative medicinal products that are not potent CYP3A4 inducers should be considered if possible.

Erlotinib and anticoagulants, coumarin derivatives

Increases in international normalized ratio (INR) and bleeding events, including isolated fatal cases, have been reported with concomitant use of erlotinib and 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 erlotinib is used concomitantly with statins.

Smoking patients

Pharmacokinetic interaction study results in non-smokers and current smokers showed that smoking reduced 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 stop smoking as early as possible before starting erlotinib treatment due to reduced erlotinib plasma concentrations with continued smoking. In the CURRENTS study, no data supported the use of a higher erlotinib dose of 300 mg in active smokers compared to the recommended dose of 150 mg. Safety data were comparable between 300 mg and 150 mg doses; however, a significant increase in the frequency of rash, interstitial lung disease, and diarrhea was observed in patients receiving higher erlotinib doses (see sections "Dosage and administration", "Special warnings and precautions for use", "Pharmacokinetics").

Erlotinib and P-glycoprotein inhibitors

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

Erlotinib and medicinal products affecting pH

Erlotinib has reduced solubility at pH values above 5. Medicinal products affecting pH in the upper gastrointestinal tract may influence erlotinib solubility and bioavailability. When erlotinib 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 maximum concentration (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 of erlotinib decreased only by 15% and 17%, respectively. The effect of antacids on erlotinib absorption has not been studied, but impaired absorption of erlotinib is possible, potentially leading to reduced plasma erlotinib levels. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is required during erlotinib treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of erlotinib. If ranitidine is prescribed, its administration should be staggered with erlotinib: erlotinib 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 plasma concentrations. In a clinical study, concomitant administration of erlotinib with carboplatin and paclitaxel resulted in a statistically significant 10.6% increase in AUC0–48 of total platinum. Despite statistical significance, this difference is considered not to have clinical relevance. 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 increase erlotinib concentrations. Following administration of erlotinib in combination with capecitabine, a statistically significant increase in erlotinib AUC and a borderline increase 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. Some clinical data and preclinical study results support this effect, showing proteasome-mediated degradation of EGFR.

Special precautions for use.

Testing for epidermal growth factor receptor (EGFR) mutations

When deciding on the use of erlotinib as first-line or maintenance treatment for locally advanced or metastatic NSCLC, it is important to determine the EGFR mutation status.

According to local medical practice, a validated, reliable and sensitive test with a defined positivity threshold and demonstrated clinical utility for determining EGFR mutation status should be used, based on tumour DNA from a tissue sample or circulating free DNA (cf-DNA) from a blood sample (plasma).

If a plasma-based cf-DNA test is used and results for activating mutations are negative, tissue testing should be performed if possible, due to the possibility of false-negative results with plasma-based testing.

Use in patients who smoke

Smokers should be advised to stop smoking, as erlotinib plasma concentrations are reduced in smokers compared to non-smokers. The degree of reduction in erlotinib plasma concentration is likely to be clinically significant (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

Interstitial lung disease

Cases of interstitial lung disease (ILD)-like events, including fatal cases, have been infrequently observed in patients with non-small cell lung cancer, pancreatic cancer or other advanced solid tumours receiving erlotinib. In the pivotal BR.21 trial in patients with non-small cell lung cancer receiving placebo or erlotinib, the incidence of ILD was 0.8% in each group. According to data from a meta-analysis of randomised controlled clinical trials in NSCLC (excluding phase I and single-arm phase II trials due to the lack of control groups), the incidence of ILD-like events was 0.9% in erlotinib treatment groups and 0.4% in control groups. In the pancreatic cancer trial using erlotinib in combination with gemcitabine, the incidence of ILD-like events in patients with pancreatic cancer receiving erlotinib and gemcitabine was 2.5% compared to 0.4% in the group receiving gemcitabine and placebo. Reported diagnoses in patients with suspected ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), lung infiltration and alveolitis. Symptoms occurred from several days to several months after initiation of erlotinib therapy. Often, confounding or predisposing factors were present, such as concomitant or prior chemotherapy, radiotherapy, underlying parenchymal lung disease, metastatic lung involvement or lung infection. A higher incidence of ILD (approximately 5%, with a mortality rate of 1.5%) has been observed in patients enrolled in studies conducted in Japan.

In patients with acute onset of new and/or progressive pulmonary symptoms of unknown origin (dyspnoea, cough, fever), erlotinib treatment should be temporarily discontinued until diagnostic evaluation is performed. Patients receiving concomitant erlotinib and gemcitabine therapy should be closely monitored for the potential development of ILD-like toxicity. In the event of ILD development, 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, symptomatic treatment (e.g. 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 increments 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. Some cases were associated with severe dehydration 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 other conditions leading to dehydration, particularly in patient groups with predisposing factors (especially with concomitant chemotherapy or other medications, presence of symptoms or diseases, or other risk factors including advanced age), erlotinib treatment should be interrupted and appropriate measures taken for intensive intravenous rehydration. Additionally, in patients at risk of dehydration, renal function and serum electrolyte levels, including potassium, should be monitored.

Hepatitis, hepatic failure

Serious cases of drug-induced liver injury (DILI), including hepatitis, acute hepatitis and hepatic failure (including fatal cases), have been reported rarely during erlotinib treatment. Factors complicating interpretation include pre-existing liver disease and concomitant use of hepatotoxic medicinal products. Therefore, periodic monitoring of liver function is required in these patients. The frequency of liver function monitoring should be increased in patients with pre-existing hepatic insufficiency or biliary obstruction. Patients reporting symptoms suggestive of liver injury should undergo immediate clinical evaluation and liver function tests. Erlotinib treatment should be interrupted in the presence of severe hepatic function abnormalities (see section "Undesirable effects"). Erlotinib treatment is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforations

Patients receiving erlotinib 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, vesicular and exfoliative skin disorders have been reported, including very rare cases of Stevens-Johnson syndrome / toxic epidermal necrolysis, some of which were fatal (see section "Undesirable effects"). Erlotinib treatment should be temporarily discontinued or permanently stopped in the event of bullous, vesicular or exfoliative skin lesions. Patients with bullous or exfoliative skin disorders should be evaluated for skin infections and treated according to local treatment guidelines.

Eye disorders

Patients presenting signs and symptoms characteristic of keratitis, such as acute onset or worsening of eye inflammation, lacrimation, photophobia, blurred vision, eye pain and/or eye redness, should be referred immediately for ophthalmological evaluation. Erlotinib treatment should be temporarily discontinued or permanently stopped if ulcerative keratitis is confirmed. The benefit-risk balance of continuing erlotinib treatment should be carefully considered in patients diagnosed with keratitis. 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 corneal ulceration. Cases of corneal perforation or ulceration during erlotinib treatment 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, while strong CYP3A4 inhibitors may increase its toxicity. Concomitant use of erlotinib with medicinal products of these types 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 erlotinib dose when co-administered with these agents can compensate for the reduced exposure. Concomitant use of erlotinib and proton pump inhibitors should be avoided. The consequences of concomitant use of erlotinib with H2-receptor antagonists and antacids are unknown, but a reduction in 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 required during erlotinib treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of erlotinib.

Excipients

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

Each film-coated tablet contains less than 1 mmol of sodium (23 mg) per tablet, i.e. essentially "sodium-free".

Disposal of unused medicine and waste medicine. Environmental contamination should be minimised. The medicine should not be disposed of via household waste or poured into wastewater. "Take-back" or collection systems should be used for disposal if available.

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient data on the use of erlotinib in pregnant women. Animal studies have shown 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 to humans is unknown. Women of reproductive potential should be advised to avoid pregnancy and to use reliable methods of contraception during treatment with erlotinib and for at least 2 weeks after the end of treatment. Treatment of a pregnant woman should only be continued 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. Studies on the effect of erlotinib on milk production or the presence of the drug in breast milk have not been conducted. Since the potential harm to breastfed infants is unknown, mothers should be advised to avoid breastfeeding during erlotinib treatment and for at least 2 weeks after the last dose.

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 to humans is unknown.

Ability to drive and use machines.

Studies on the effect on the ability to drive or operate machinery have not been conducted, but erlotinib use is not associated with cognitive impairment.

Method of Administration and Dosage

Treatment with Fokleros® should be prescribed and supervised by a physician experienced in anticancer therapy.

Non-small cell lung cancer

Testing for epidermal growth factor receptor (EGFR) mutations must be performed (see section "Indications").

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

Pancreatic cancer

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

If a patient does not develop rash within the first 4–8 weeks of treatment, the continuation of erlotinib therapy should be reconsidered (see section "Pharmacodynamics").

If dose adjustment is required, the dose should be reduced stepwise by 50 mg (see section "Special precautions for use"). Dose modification may also be necessary when erlotinib is co-administered with substrates or modulators of CYP3A4 (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 similar in patients with moderate hepatic impairment (Child–Pugh score 7–9) and those with normal liver function, caution should be exercised when administering erlotinib to patients with hepatic insufficiency. In case of severe adverse reactions, the dose of erlotinib 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. Erlotinib is not recommended for use in patients with severe hepatic impairment (see section "Pharmacokinetics").

Renal impairment

The safety and efficacy of erlotinib in patients with renal impairment (serum creatinine concentration more than 1.5 times ULN) have not been studied. Based on pharmacokinetic data, dose adjustment is not necessary for patients with mild to moderate renal impairment (see section "Pharmacokinetics"). Erlotinib is not recommended for use in patients with severe renal impairment.

Use in smokers

Smoking has been shown to reduce erlotinib exposure by 50–60%. The maximum tolerated dose of erlotinib in current smokers with non-small cell lung cancer is 300 mg. Improved efficacy of the 300 mg dose has not been demonstrated in second-line treatment following failed chemotherapy compared to the recommended 150 mg dose in patients who continue to smoke. Safety profiles of the 300 mg and 150 mg doses were comparable; however, patients receiving the higher erlotinib dose experienced a significantly increased incidence of rash, interstitial lung disease, and diarrhea. Patients who continue to smoke are advised to quit (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

Children

The safety and efficacy of erlotinib for the approved indications in patients under 18 years of age have not been established. Erlotinib is not recommended for use in pediatric patients.

Overdose

Symptoms

Single oral doses of erlotinib up to 1000 mg in healthy volunteers and up to 1600 mg in cancer patients were 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 such as diarrhea, rash, and possibly elevated levels of hepatic aminotransferases.

Management

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

Adverse reactions.

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

Information on the frequency of adverse reactions from clinical trials of erlotinib used either as monotherapy or in combination with chemotherapy is presented below according to NCI-CTC (National Cancer Institute Common Toxicity Criteria [USA]). Reported adverse reactions are those occurring with a frequency of at least 10% (in the erlotinib treatment group) and more frequently (≥3%) in patients receiving erlotinib compared to the control group.

Adverse reactions observed in clinical trials (see below) are listed by organ system class (MedDRA [Medical Dictionary for Regulatory Activities] classification). The criteria used to define frequency of adverse reactions are: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Non-small cell lung cancer (erlotinib monotherapy)

First-line treatment in patients with EGFR mutations

In an open-label, randomized Phase III study (ML20650), the safety of erlotinib in first-line treatment of patients with NSCLC and activating EGFR mutations was evaluated in 75 patients; no new safety signals were observed in these patients.

The most common adverse reactions in patients receiving erlotinib in study ML20650 were rash and diarrhea (any grade: 80% and 57%, respectively), the majority of which were Grade 1/2 in severity and did not require intervention. Grade 3 rash and diarrhea were observed in 9% and 4% of patients, respectively. Grade 4 rash and diarrhea were not observed. Rash and diarrhea led to discontinuation of therapy in 1% of patients. Dose modification (treatment interruption or dose reduction) due to rash and diarrhea was required in 11% and 7% of patients, respectively.

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 studies included a total of 1532 patients with advanced, recurrent, or metastatic NSCLC after standard platinum-based first-line chemotherapy. No new safety signals were identified.

The most common adverse reactions observed in patients receiving erlotinib in studies BO18192 and BO25460 were rash (BO18192: all grades — 49.2%, Grade 3 — 6%; BO25460: all grades — 39.4%, Grade 3 — 5%) and diarrhea (BO18192: all grades — 20.3%, Grade 3 — 1.8%; BO25460: all grades — 24.2%, Grade 3 — 2.5%). No Grade 4 rash or diarrhea events were observed in either study. Rash and diarrhea led to premature discontinuation of erlotinib in 1% and <1% of patients, respectively, in study BO18192; in study BO25460, no premature discontinuation of erlotinib due to rash or diarrhea was observed. Dose modification (treatment interruption or dose reduction) due to rash and diarrhea was required in 8.3% and 3% of patients, respectively, in study BO18192, and in 5.6% and 2.8% of patients, respectively, in study BO25460.

Second and further lines of treatment

In the randomized, double-blind trial BR.21 (erlotinib used in second-line therapy), the most common adverse reactions were rash (75%) and diarrhea (54%), the majority of which were Grade 1 or 2 in severity and resolved without intervention. Grade 3/4 rash and diarrhea were observed in 9% and 6% of patients with non-small cell lung cancer receiving erlotinib, respectively, and each of these reactions led to study withdrawal in 1% of patients and required dose modification in 6% and 1% of patients, respectively. In study BR.21, the median time to onset of rash was 8 days, and to onset of diarrhea was 12 days. Overall, erythematous and papulopustular rashes of mild to moderate severity were observed, occurring or worsening in sun-exposed skin areas.

Patients exposed to sunlight are advised to wear protective clothing and/or use sun protection agents (e.g., mineral-based sunscreens).

Pancreatic cancer (concomitant use of erlotinib with gemcitabine)

The most common adverse reactions in the pivotal trial PA.3 in patients with pancreatic cancer who received erlotinib 100 mg in combination with gemcitabine were fatigue, rash, and diarrhea. In the erlotinib plus gemcitabine group, Grade 3/4 rash and diarrhea occurred in 5% of patients. The median time to onset of rash was 10 days, and to onset of diarrhea was 15 days. These reactions required dose reduction in 2% of patients or led to premature withdrawal from the study in less than 1% of patients receiving erlotinib in combination with gemcitabine.

Below are listed adverse reactions occurring in ≥10% of patients in trials BR.21 (erlotinib monotherapy) and PA.3 (combination therapy with erlotinib plus gemcitabine), and adverse reactions occurring more frequently (≥3%) than in the placebo group in trials BR.21 (erlotinib monotherapy) and PA.3 (combination therapy with erlotinib plus gemcitabine).

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

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

*** Skin eruptions include acneiform dermatitis.

• Corresponds to the percentage below the specified threshold.

Other adverse reactions, including those observed in other clinical studies, by frequency category are listed below.

1 In clinical study PA.3.

2 Including eyelash growth, excessive growth, and eyelash thickening.

3 Including fatal cases in patients receiving erlotinib for the treatment of NSCLC or other common solid tumors (see section "Special precautions for use"). Observed more frequently in patients in Japan (see section "Special precautions for use").

4 In clinical studies, in some cases associated with concomitant use of warfarin and in some cases with concomitant use of NSAIDs (see section "Interaction with other medicinal products and other forms of interaction").

5 Including increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. This phenomenon was very common in clinical study PA.3 and common in clinical study BR.21. Most cases were of mild or moderate severity, transient in nature, or associated with liver metastases.

6 Including fatal cases. Factors complicating interpretation included underlying liver disease or concomitant use of hepatotoxic medicinal products (see section "Special precautions for use").

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

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. This enables continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua/.

Shelf life.

3 years.

Storage conditions.

This medicinal product does not require special storage conditions.

Keep out of the reach and sight of children.

Packaging.

6 tablets in a blister, 5 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.