Erlotinib-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERLOTINIB-VISTA (ERLOTINIB-VISTA)

Composition:

Active substance: erlotinib;

One film-coated tablet contains erlotinib hydrochloride 54.63 mg, equivalent to erlotinib 50 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); magnesium stearate;

Film coating: polyvinyl alcohol; titanium dioxide (E 171); macrogol; talc; methacrylic acid copolymer (type A); sodium bicarbonate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: white to yellowish, round, biconvex, film-coated tablets, with the imprint "50" on one side.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Erlotinib. ATC code L01E B02.

Pharmacological properties.

Pharmacodynamics.

Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), also known as human epidermal growth factor receptor type 1 (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 the strong binding of erlotinib to the ATP-binding site in the mutated kinase domain of EGFR. 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. A study in healthy volunteers estimated the absolute bioavailability of the drug to be 59%. Exposure after oral administration may be increased by food.

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 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 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 maximum plasma concentration at steady state. 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 cytochrome P450 enzymes, primarily by CYP3A4, 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 the metabolic clearance of erlotinib. Metabolism occurs 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 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 monotherapy showed that the mean apparent clearance is 4.47 L/h, with a median elimination half-life of 36.2 hours. Therefore, it can be expected that the time to reach steady-state plasma concentration is approximately 7–8 days.

Pharmacokinetics in special patient populations.

Population pharmacokinetic analysis data showed no clinically relevant dependencies between predicted apparent clearance and patient age, body weight, sex, 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 concentrations were associated with decreased erlotinib clearance. The clinical significance of this observation is unknown. However, accelerated clearance of erlotinib is observed in smokers, 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 (Cmax) was 1056 ng/mL in non-smokers and 689 ng/mL in smokers, with a mean ratio of non-smokers to smokers of 65.2% (95% CI: 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 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 non-smokers and 34.8 ng/mL in smokers, with a mean ratio of 12.1% (95% CI: 4.82–30.2; p = 0.0001). In the pivotal phase III 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 times lower than in former smokers/non-smokers (1.28 µg/mL, n = 108). This was associated with a 24% increase in plasma clearance of erlotinib. In a phase I dose-escalation study involving 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 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, smokers are advised to stop smoking during erlotinib treatment, as otherwise a reduction in plasma concentration of the drug may occur.

According to population pharmacokinetic analysis data, erlotinib exposure increased by approximately 11% in the presence of opioids.

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 the 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 the plasma clearance of erlotinib.

Children.

Specific studies in children have not been conducted.

Elderly patients.

Specific studies in elderly patients have not been conducted.

Hepatic impairment.

Erlotinib clearance occurs primarily via the liver. 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 hepatic 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 relevant. There are no data on the effect of severe hepatic dysfunction on the pharmacokinetics of erlotinib. In population pharmacokinetic analysis, increased serum total bilirubin concentration was associated with slower erlotinib elimination.

Renal impairment.

Erlotinib and its metabolites are excreted in small amounts via the kidneys: less than 9% of a single dose is excreted in urine. In population pharmacokinetic analysis, no clinically significant association 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) harboring EGFR-activating mutations.

Erlotinib-Vista is also indicated for 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 at least one prior chemotherapy regimen. Erlotinib-Vista is indicated for patients with tumors lacking EGFR-activating mutations when other treatment options are not suitable.

When prescribing Erlotinib-Vista, factors associated with 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 receptor (EGFR) expression as determined by immunohistochemical analysis.

Pancreatic cancer.

Treatment of metastatic pancreatic cancer in combination with gemcitabine. When prescribing Erlotinib-Vista, factors associated with 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 were conducted only in adult patients.

Erlotinib and other CYP substrates.

Erlotinib is a potent inhibitor of CYP1A1 and a moderate to 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 co-administered with ciprofloxacin, a moderate inhibitor of CYP1A2, erlotinib exposure (AUC) increased by 39%, while maximum concentration (Cmax) did not change significantly. Similarly, exposure (AUC) of active metabolites increased by 60% and 48% for AUC and Cmax, respectively. The clinical significance of this increased exposure has not been established. Therefore, caution is advised when prescribing erlotinib with ciprofloxacin or potent CYP1A2 inhibitors (e.g., fluvoxamine). If erlotinib-related adverse reactions occur, the dose of the medicinal product may be reduced.

Prior or concomitant treatment with erlotinib did not alter the clearance of prototype 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 administered concomitantly. Therefore, clinically significant interactions affecting 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 solely via this metabolic pathway. Patients with low UGT1A1 expression or genetically determined disorders of glucuronidation (e.g., Gilbert's syndrome) may experience increased serum bilirubin concentrations; therefore, caution is required in their treatment.

Erlotinib is metabolized in the liver primarily by hepatic cytochromes, mainly CYP3A4 enzymes, 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 may occur with active substances metabolized by these enzymes or those acting as 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 increased erlotinib exposure (by 86% in AUC and by 69% in Cmax). Caution is advised when prescribing Erlotinib-Vista with potent CYP3A4 inhibitors, including azole antifungals (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, clarithromycin. If toxicity develops, the dose of Erlotinib-Vista 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, reduced median erlotinib AUC by 69%. When rifampicin was co-administered with a single 450 mg dose of erlotinib, mean erlotinib exposure (A游戏副本) was 57.5% of that observed after a single 150 mg dose of erlotinib without rifampicin therapy. Concomitant use of Erlotinib-Vista and CYP3A4 inducers should be avoided. For patients requiring concomitant treatment with erlotinib and a potent CYP3A4 inducer (such as rifampicin), dose escalation of Erlotinib-Vista up to 300 mg with careful monitoring of the patient (including renal and hepatic function and serum electrolytes) should be considered. If well tolerated for more than 2 weeks, the dose of Erlotinib-Vista 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). Use of these agents in combination with erlotinib requires caution. Where possible, alternative medicinal products that are not potent CYP3A4 inducers should be prescribed.

Erlotinib and anticoagulants, coumarin derivatives.

Elevated 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. Patients receiving coumarin-derived anticoagulants should have prothrombin time or INR 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.

Erlotinib and smoking patients.

Pharmacokinetic study results in non-smokers and current smokers showed that smoking reduces AUCinf, Cmax, and 24-hour plasma concentration of erlotinib by 2.8-, 1.5-, and 9-fold, respectively. Therefore, smokers should be advised to quit smoking as early as possible before starting erlotinib therapy due to reduced erlotinib plasma concentrations with continued smoking. Based on results from the CURRENTS study, no evidence supported the use of a higher erlotinib dose of 300 mg versus the recommended 150 mg dose in active smokers. 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 "Method of administration and dosage," "Special instructions," "Pharmacokinetics").

Erlotinib and P-glycoprotein inhibitors.

Erlotinib is a substrate of the P-glycoprotein drug transporter. Concomitant administration of erlotinib with P-glycoprotein inhibitors (e.g., cyclosporine, verapamil) may alter erlotinib distribution and/or elimination. The consequences of such interactions, particularly for 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 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 medicinal products is unlikely to compensate for reduced exposure. However, when erlotinib was administered 2 hours before or 10 hours after ranitidine (150 mg twice daily), AUC and Cmax 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 levels. Therefore, combination 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 relative to erlotinib: the medicinal product 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 concentration in plasma. In a clinical study, concomitant administration of erlotinib with carboplatin and paclitaxel resulted in a statistically significant increase in total platinum AUC0-48 by 10.6%, though this is not considered clinically relevant. 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 marginal 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 mechanism of action, proteasome inhibitors, including bortezomib, are expected to affect the activity of epidermal growth factor receptor (EGFR) inhibitors, including erlotinib. Limited clinical data and preclinical study results showing proteasome-mediated degradation of EGFR support this potential interaction.

Special precautions.

Testing for epidermal growth factor receptor (EGFR) mutations. When deciding on the use of Erlotinib-Vista as first-line or maintenance therapy 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 utility for determining EGFR mutation status should be used, employing tumor DNA from a tissue sample or cell-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 extent of reduction in erlotinib plasma concentration is likely to be clinically significant (see sections "Method of administration and dosage", "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

Interstitial lung disease.

Cases of interstitial lung disease (ILD)-like events, including fatal ILD, have been infrequently observed in patients with non-small cell lung cancer, pancreatic cancer, or other advanced solid tumors receiving erlotinib. In the pivotal BR.21 study 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 randomized controlled clinical trials in NSCLC (excluding phase I and single-arm phase II trials due to 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 study using erlotinib in combination with gemcitabine, the incidence of ILD-like events in patients receiving erlotinib and gemcitabine was 2.5%, compared to 0.4% in patients receiving gemcitabine and placebo. Reported diagnoses in patients with suspected ILD-like events included pneumonia, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), lung infiltration, and alveolitis. Symptoms appeared 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 fatality 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 respiratory symptoms of unknown origin (dyspnea, cough, fever), erlotinib treatment should be temporarily discontinued pending diagnostic evaluation. Patients receiving concomitant erlotinib and gemcitabine therapy should be closely monitored for potential development of ILD-like toxicity. In the event of ILD development, erlotinib should be discontinued and appropriate treatment initiated if necessary (see section "Adverse reactions").

Diarrhea, dehydration, electrolyte imbalance, and renal failure.

Diarrhea (including very rare cases with fatal outcome) was observed in approximately 50% of patients receiving erlotinib therapy. In cases of severe or moderate diarrhea, treatment with, for example, loperamide should be initiated. In some cases, dose reduction of the drug may be necessary. During clinical trials, doses were reduced in 50 mg steps. Dose reductions in 25 mg increments have not been studied. Erlotinib-Vista treatment should be suspended in cases of severe or persistent diarrhea, nausea, anorexia, or vomiting accompanied by dehydration, and appropriate measures taken to correct dehydration (see section "Adverse reactions"). Hypokalemia and renal failure (including fatal cases) have been rarely reported. In some cases, dehydration was caused by diarrhea, vomiting, and/or anorexia, while in others, interpretation was complicated by concomitant chemotherapy. In more severe or persistent cases of diarrhea or cases leading to dehydration, especially in patient groups with risk factors (concomitant use of other medicinal products, presence of symptoms or diseases, or other predisposing factors, including advanced age), treatment with Erlotinib-Vista should be interrupted and appropriate measures taken for intensive intravenous rehydration. In patients at risk of dehydration, renal function and serum electrolyte levels, including potassium, should also be monitored.

Hepatotoxicity.

Serious cases of drug-induced liver injury, including hepatitis, acute hepatitis, and hepatic failure (including fatal cases), have been reported during erlotinib therapy. Factors complicating interpretation include pre-existing liver disease and concomitant use of hepatotoxic medicinal products. Periodic monitoring of liver function is recommended during erlotinib treatment. The frequency of liver function monitoring should be increased in patients with pre-existing hepatic insufficiency or biliary obstruction. Patients reporting possible symptoms should undergo immediate clinical evaluation and liver function tests.

Erlotinib-Vista treatment should be suspended in case of marked abnormalities in liver function (see section "Adverse reactions"). Erlotinib-Vista is not recommended for patients with severe hepatic impairment.

Gastrointestinal perforation.

Patients taking Erlotinib-Vista are at increased risk of gastrointestinal perforation, which occurs infrequently (including isolated fatal cases). Increased risk of gastrointestinal perforation is observed 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-Vista treatment should be permanently discontinued in the event of gastrointestinal perforation (see section "Adverse reactions").

Bullous and exfoliative skin disorders.

Bullous, vesicular, and exfoliative skin disorders, including very rare cases of Stevens-Johnson syndrome/toxic epidermal necrolysis, some of which were fatal, have been observed during erlotinib therapy (see section "Adverse reactions"). In the event of such bullous, vesicular, or exfoliative skin disorders, Erlotinib-Vista treatment should be temporarily discontinued or permanently stopped. Patients with bullous and exfoliative skin disorders should be evaluated for skin infections and treated according to local treatment guidelines.

Ocular disorders.

Patients presenting signs and symptoms characteristic of keratitis, namely acute onset or worsening of the following conditions: eye inflammation, lacrimation, photophobia, blurred vision, eye pain, and/or eye redness, should be immediately referred for ophthalmological consultation. Erlotinib treatment should be temporarily or permanently discontinued upon confirmation of ulcerative keratitis. The benefit-risk balance of continuing Erlotinib-Vista 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 therapy have been very rarely reported (see section "Adverse reactions").

Interaction with other medicinal products.

Potent inducers of CYP3A4 enzymes may reduce erlotinib efficacy, whereas potent CYP3A4 inhibitors may lead to increased toxicity. Concomitant use of Erlotinib-Vista 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 values above 5. Medicinal products that alter pH in the upper gastrointestinal tract (GI tract), such as proton pump inhibitors, H2-receptor antagonists, and antacids, may affect erlotinib solubility and, consequently, its bioavailability. It is unlikely that increasing the erlotinib dose during concomitant use of these agents can compensate for reduced exposure. Concomitant use of Erlotinib-Vista 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 during Erlotinib-Vista treatment, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib-Vista.

Important information on excipients.

Erlotinib-Vista 50 mg film-coated tablets contain lactose.

If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

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 potential negative effect on pregnancy cannot be ruled out, as increased embryofetal mortality was observed in studies conducted on rats and rabbits. The potential risk to humans is unknown.

Women of childbearing potential.

Women of reproductive age should avoid pregnancy and use reliable methods of contraception during treatment with Erlotinib-Vista and for at least 2 weeks after completion of therapy. Treatment during pregnancy should be continued only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

It is unknown whether erlotinib is excreted in human breast milk. Studies on the effect of erlotinib on milk production or its presence in breast milk have not been conducted. Because the potential harm to breastfed infants is unknown, women should discontinue breastfeeding during treatment with the medicinal product and for at least 2 weeks after receiving the last dose.

Fertility.

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

Ability to influence reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

Treatment with Erlotinib-Vista should be administered by a physician experienced in anticancer therapy.

Non-small cell lung cancer.

Prior to initiating treatment with Erlotinib-Vista, patients with advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy should be tested for epidermal growth factor receptor (EGFR) mutations.

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

Pancreatic cancer.

The recommended dose of Erlotinib-Vista is 100 mg once daily, taken 1 hour before or 2 hours after a meal, in combination with gemcitabine (see also the gemcitabine prescribing information, indication – pancreatic cancer).

If a patient does not develop rash within the first 4–8 weeks of treatment, continuation of therapy with Erlotinib-Vista 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"). Dose adjustment may be necessary when co-administering substrates and 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 approximately similar in patients with moderate hepatic impairment (Child-Pugh score 7–9) compared to those with normal hepatic function, caution should be exercised when administering Erlotinib-Vista to patients with hepatic insufficiency. If severe adverse reactions occur, the dose of Erlotinib-Vista should be reduced or treatment discontinued. The safety and efficacy of Erlotinib-Vista in patients with severe hepatic impairment (AST/SGOT [aspartate aminotransferase/serum glutamic-oxaloacetic transaminase] and ALT/SGPT [alanine aminotransferase/serum glutamic-pyruvic transaminase] >5× upper limit of normal [ULN]) have not been studied; therefore, erlotinib is not recommended in such patients (see section "Pharmacokinetics").

Renal impairment.

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

Use in smokers.

Smoking reduces erlotinib exposure by 50–60%. The maximum tolerated dose of Erlotinib-Vista in patients with non-small cell lung cancer who smoke is 300 mg.

A dose of 300 mg did not demonstrate improved efficacy in second-line treatment following ineffective chemotherapy compared to the recommended dose of 150 mg in patients who continue to smoke. Safety data were comparable between the 300 mg and 150 mg doses; however, patients receiving the higher erlotinib dose experienced a significant increase in the frequency of rash, interstitial lung disease, and diarrhea.

Therefore, patients who continue to smoke are advised to quit smoking (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

Children.

The safety and efficacy of erlotinib in patients under 18 years of age have not been established for the approved indications. Use of Erlotinib-Vista 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.

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.

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

First-line treatment of patients with EGFR mutations.

In an open-label, randomized Phase III trial (ML20650), 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 commonly reported adverse reactions in patients treated with erlotinib in study ML20650 were rash and diarrhea, most of which were Grade 1/2 in severity and did not require intervention.

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 first-line platinum-based chemotherapy.

The most commonly observed adverse reactions in patients treated with erlotinib in trials BO18192 and BO25460 were rash and diarrhea.

Second and further lines of treatment.

In the randomized, double-blind trial BR.21 (erlotinib used in second-line therapy), the most commonly reported adverse reactions were rash and diarrhea, most of which were Grade 1 or 2 in severity and resolved without intervention. In trial BR.21, the median time to onset of rash was 8 days and to onset of diarrhea was 12 days.

Pancreatic cancer (concomitant use of erlotinib with gemcitabine).

The most commonly reported 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. The median time to onset of rash was 10 days and to onset of diarrhea was 15 days.

Adverse reaction table.

Table 1 summarizes adverse reactions reported during clinical trials and post-marketing surveillance with erlotinib used alone or in combination with chemotherapy. Adverse reactions are classified by organ systems according to MedDRA (Medical Dictionary for Regulatory Activities). Frequency of adverse reactions is defined as follows: 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 group, adverse reactions are listed in order of decreasing severity.

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

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

Description of selected adverse reactions.

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).

Diarrhea.

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

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

Infection.

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

Changes in eyelashes.

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

Interstitial lung disease (ILD).

ILD includes fatal cases in patients who received erlotinib for the treatment of NSCLC or other progressive solid tumors. A higher incidence was 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 tract 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 suspected adverse reactions after registration of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk ratio for the respective medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life.

4 years.

Storage conditions.

No special temperature storage conditions are required for this medicinal product. Keep out of reach of children.

Packaging.

10 tablets of 50 mg; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Remedica Limited

Manufacturer's address and location of its business operations.

Acharnon Street, Limassol Industrial Estate, Limassol, 3056, Cyprus