Erlotinib krka

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERLONAT KRKA (Erlotinib KRKA)

Composition:

Active substance: erlotinib;

One film-coated tablet contains 25 mg, 100 mg, or 150 mg of erlotinib in the form of erlotinib hydrochloride;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, sodium lauryl sulfate, sodium starch glycolate (type A), calcium silicate, magnesium stearate;

Film coating: coating mixture: hypromellose, titanium dioxide (E 171), talc, propylene glycol; iron oxide red (E 172) – only for 100 mg tablets; iron oxide yellow (E 172) – only for 25 mg and 100 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: pale yellow, round, slightly biconvex, film-coated tablets with beveled edges and engraved "25" on one side.

100 mg tablets: pale orange-pink, round, slightly biconvex, film-coated tablets with beveled edges and engraved "100" on one side.

150 mg tablets: white or almost white, round, biconvex, film-coated tablets with beveled edges and engraved "150" on one side.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR). 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 tyrosine phosphorylation leads to cell growth arrest and cell death.

EGFR-activating 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 (Cmax) of erlotinib is reached approximately 4 hours after oral administration. A study involving healthy volunteers estimated the absolute bioavailability of the drug to be 59%. Oral exposure may be increased under the influence of food.

Distribution

Erlotinib has a mean apparent volume of distribution of 232 L and distributes into human tumor tissues. In a study involving 4 patients (3 with non-small cell lung cancer [NSCLC] and 1 with laryngeal cancer) who received Erlotinib KRKA at a dose of 150 mg daily, tumor samples obtained during surgery on day 9 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 the tumor at a mean concentration of 160 ng/g, corresponding to an overall mean of 113% (range 88–130%) of the steady-state maximum plasma concentration. 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, 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 contribute to 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 phenylacetylene group. The primary metabolites of erlotinib, OSI-420 and OSI-413, formed by O-demethylation of one of the side chains, exhibit 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.

Excretion

Erlotinib metabolites are primarily excreted in feces (>90%), with a small amount of the orally administered dose excreted by 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 KRKA as monotherapy showed a mean apparent clearance of 4.47 L/hour 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 did not reveal any clinically significant relationships between predicted apparent clearance and patient age, body weight, gender, or ethnicity. Erlotinib pharmacokinetics were influenced by serum total bilirubin concentration, AAG, and current smoking status. Decreased erlotinib clearance was observed with increased serum total bilirubin and AAG concentrations. The clinical significance of this observation is unknown. However, accelerated erlotinib clearance was observed in smokers, 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 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 concentration (C24h) 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 a phase III pivotal study in NSCLC patients who smoked, the minimum steady-state plasma concentration was 0.65 µg/mL (n=16), which is two-fold 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 following dose escalation of Erlotinib KRKA from 150 mg to the maximum tolerated dose of 300 mg. The steady-state minimum plasma concentration after 300 mg dose in continuing smokers in this study was 1.22 µg/mL (n=17) (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use", "Dosage and Administration").

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

According to population pharmacokinetic analysis, concomitant use of opioid medications increases 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 children have not been conducted.

Elderly Patients

Specific studies in elderly patients have not been conducted.

Hepatic Impairment

Erlotinib is predominantly eliminated by the liver. In patients with solid tumors and moderate hepatic impairment (Child-Pugh score 7–9), geometric mean AUC0-t and Cmax values 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 small amounts—less than 9% of a single dose. In population pharmacokinetic analysis, no clinically significant relationship 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)

First-line treatment of patients with locally advanced or metastatic NSCLC harboring EGFR-activating mutations.

Erlotinib KRKA is also indicated for maintenance treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations whose disease has not progressed after first-line chemotherapy.

Erlotinib KRKA is also indicated for the treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. In patients with tumors lacking EGFR-activating mutations, Erlotinib KRKA is indicated when other treatment options are not suitable.

When prescribing Erlotinib KRKA, 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) expression as determined by immunohistochemical testing.

Pancreatic cancer

Treatment of metastatic pancreatic cancer in combination with gemcitabine.

When prescribing Erlotinib KRKA, factors related to prolonged survival should be considered.

Survival benefit has not 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 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.

Concomitant administration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP1A2, increased erlotinib exposure (AUC) by 39%, while Cmax did not change significantly. Similarly, 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 KRKA with ciprofloxacin or potent CYP1A2 inhibitors (e.g., fluvoxamine). If erlotinib-related adverse reactions occur, the dose may be reduced.

Prior or concomitant treatment with Erlotinib KRKA 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 did not affect the pharmacokinetics of the CYP3A4/2C8 substrate paclitaxel when coadministered. Therefore, clinically significant interactions affecting clearance of other CYP3A4 substrates are unlikely.

Inhibition of glucuronidation may lead to interactions with medicinal products that are UGT1A1 substrates and are eliminated exclusively via this metabolic pathway. Increased serum bilirubin concentrations may occur in patients with low UGT1A1 expression or genetically determined glucuronidation disorders (e.g., Gilbert’s syndrome); therefore, caution is required in treating such patients.

Erlotinib is metabolized in the liver primarily by CYP3A4 enzymes, to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in the small intestine, CYP1A1 in the lungs, and CYP1B1 in tumor tissue may also contribute to erlotinib metabolic clearance. Potential interactions are possible with active substances that are metabolized by these enzymes or that act 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 an 86% increase in erlotinib exposure (AUC) and a 69% increase in Cmax. Caution is advised when prescribing Erlotinib KRKA with potent CYP3A4 inhibitors, including azole antifungals (ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin, clarithromycin. If toxicity develops, the dose of Erlotinib KRKA 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 coadministered with a single 450 mg dose of Erlotinib KRKA, mean erlotinib exposure (AUC) was 57.5% of that observed after a single 150 mg dose of Erlotinib KRKA in the absence of rifampicin therapy. Concomitant use of Erlotinib KRKA and CYP3A4 inducers should be avoided. For patients requiring concomitant treatment with Erlotinib KRKA and a potent CYP3A4 inducer (e.g., rifampicin), dose escalation of Erlotinib KRKA up to 300 mg should be considered with careful monitoring of the patient (including renal and hepatic function and serum electrolyte levels). If the drug is well tolerated for more than 2 weeks, the dose may be increased to 450 mg with careful safety monitoring. Reduced erlotinib exposure is possible when coadministered with other CYP3A4 inducers (phenytoin, carbamazepine, barbiturates, St. John’s wort-containing products). Concomitant use of these medicinal products with erlotinib requires caution. Where possible, alternative agents that are not potent CYP3A4 inducers should be prescribed.

Erlotinib and anticoagulants, coumarin derivatives

Increased international normalized ratio (INR) and bleeding, including isolated cases with fatal outcome, have been reported during concomitant use of Erlotinib KRKA and coumarin-derived anticoagulants, including warfarin. Patients receiving coumarin-derived anticoagulants should have their 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 KRKA is used concomitantly with statins.

Erlotinib and smoking patients

Pharmacokinetic study results in non-smokers and current smokers showed that smoking reduced AUCinf, Cmax, and 24-hour plasma concentration of erlotinib by 2.8-, 1.5-, and 9-fold, respectively. Therefore, smokers should be strongly encouraged to stop smoking as early as possible before starting treatment with Erlotinib KRKA due to reduced plasma concentrations of erlotinib with continued smoking. Based on data from the CURRENTS study, no benefit was demonstrated with a higher erlotinib dose of 300 mg compared to the recommended dose of 150 mg in active smokers. Safety data were comparable between 300 mg and 150 mg doses, although a notable increase in the frequency of rash, interstitial lung disease, and diarrhea was observed in patients receiving higher erlotinib doses (see sections "Pharmacokinetics", "Special instructions", "Method of administration and dosage").

Erlotinib and P-glycoprotein inhibitors

Erlotinib is a substrate of the P-glycoprotein transporter. Concomitant administration of Erlotinib KRKA and 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 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. Concomitant administration of Erlotinib KRKA with omeprazole, a proton pump inhibitor, reduced erlotinib AUC and Cmax by 46% and 61%, respectively. Tmax and elimination half-life were unchanged. When Erlotinib KRKA was administered concomitantly with ranitidine (300 mg), an H2-receptor antagonist, erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Increasing the dose of Erlotinib KRKA is unlikely to compensate for reduced exposure when coadministered with such agents. However, when Erlotinib KRKA was administered 2 hours before or 10 hours after ranitidine (150 mg twice daily), erlotinib 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 erlotinib levels. Therefore, concomitant use of erlotinib with proton pump inhibitors should be avoided. If antacid therapy is required during treatment with Erlotinib KRKA, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib KRKA. If ranitidine is prescribed, its administration should be staggered with erlotinib: 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 concentration in plasma. 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, but this was 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 lead to increased erlotinib concentrations. After erlotinib administration 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 administered 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, may affect the activity of epidermal growth factor receptor (EGFR) inhibitors, including erlotinib. Limited clinical data and preclinical study results suggest such an effect, showing proteasome-mediated degradation of EGFR.

Special precautions for use.

Testing for epidermal growth factor receptor mutations

When considering the use of Erlotinib KRKA as first-line treatment or maintenance treatment of locally advanced or metastatic NSCLC, it is important to determine the patient's EGFR mutation status.

A well-validated, reliable and sensitive test with a predefined positivity threshold for determining EGFR mutation status, using either tumour DNA obtained from a tissue sample or circulating free DNA (cfDNA) obtained from a blood (plasma) sample, should be performed according to local medical practice.

If a plasma-based cfDNA test is used and the result is negative for activating mutations, 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 “Pharmacokinetics”, “Interaction with other medicinal products and other forms of interaction”).

Interstitial lung disease

Cases of interstitial lung disease (ILD)-like events, including fatal events, have been infrequently observed in patients with NSCLC, pancreatic cancer or other advanced solid tumours receiving Erlotinib KRKA. In the pivotal BR.21 study in patients with NSCLC receiving placebo or Erlotinib KRKA, the incidence of ILD was 0.8% in each group. The incidence of ILD-like events in patients with pancreatic cancer receiving Erlotinib KRKA and gemcitabine was 2.5% compared to 0.4% in the group receiving gemcitabine and placebo. The overall incidence of ILD-like events in patients receiving Erlotinib KRKA, including in uncontrolled trials and trials with concomitant chemotherapy, is 0.6% compared to 0.2% in patients receiving placebo. 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, which occurred from several days to several months after initiation of Erlotinib KRKA therapy. Often, factors associated with concomitant or prior chemotherapy, radiotherapy, pre-existing parenchymal lung disease, metastatic lung involvement or infection were present. A high incidence of ILD (approximately 5% with a mortality rate of 1.5%) was observed among patients of Japanese origin.

In the event of new and/or worsening respiratory symptoms of unknown origin (dyspnoea, cough and fever), treatment with Erlotinib KRKA should be temporarily discontinued until the cause is determined. Patients receiving concomitant treatment with erlotinib and gemcitabine should be closely monitored for the potential development of ILD-like toxicity. If ILD develops, Erlotinib KRKA should be discontinued and appropriate treatment initiated (see section “Adverse reactions”).

Diarrhoea, dehydration, electrolyte imbalance and renal failure

Diarrhoea (including very rare fatal cases) was observed in approximately 50% of patients receiving treatment with Erlotinib KRKA. In the event of severe or moderate diarrhoea, treatment with, for example, loperamide should be initiated. In some cases, dose reduction of the medicinal product may be necessary. In clinical trials, the dose was reduced in 50 mg steps. Dose reduction in 25 mg steps has not been studied. In cases of severe or persistent diarrhoea, nausea, anorexia or vomiting accompanied by dehydration, treatment with Erlotinib KRKA should be interrupted and appropriate measures taken to correct dehydration (see section “Adverse reactions”). Hypokalaemia and renal failure (including fatal cases) have been rarely reported. Some cases were due to severe dehydration resulting from diarrhoea, vomiting and/or anorexia, while in others the interpretation was complicated by concomitant chemotherapy. In more severe or persistent cases of diarrhoea or cases leading to dehydration, particularly in patient groups with predisposing risk factors (concomitant use of other drugs, presence of symptoms or diseases, or other predisposing factors, including advanced age), treatment with Erlotinib KRKA 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 (DILI), including hepatitis, acute hepatitis and liver failure (including fatal cases), have been reported during erlotinib treatment. Risk factors may include pre-existing liver disease or concomitant use of hepatotoxic drugs. Liver function should be periodically monitored during erlotinib treatment. Monitoring of liver function should be increased in frequency in patients with pre-existing liver impairment or biliary obstruction. Patients reporting symptoms suggestive of liver injury should undergo immediate clinical evaluation and liver function tests. Treatment with Erlotinib KRKA should be interrupted in the presence of marked abnormalities in liver function (see section “Adverse reactions”). The use of the medicinal product is not recommended in patients with severe hepatic impairment.

Gastrointestinal perforations

Patients taking Erlotinib KRKA are at increased risk of gastrointestinal perforation, which occurs infrequently (including individual fatal cases). Increased risk of gastrointestinal perforation has been observed in patients receiving concomitant treatment 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. In the event of gastrointestinal perforation, treatment with Erlotinib KRKA should be permanently discontinued (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, have been observed during treatment with Erlotinib KRKA, some of which were fatal (see section “Adverse reactions”). In the event of bullous, vesicular or exfoliative skin disorders, treatment with Erlotinib KRKA should be temporarily discontinued or stopped. Patients with bullous and exfoliative skin disorders should be evaluated for skin infections and treated according to local treatment guidelines.

Eye disorders

Patients experiencing 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 referred immediately for ophthalmological consultation. In the event of confirmed ulcerative keratitis, treatment with Erlotinib KRKA should be temporarily discontinued or permanently discontinued. The benefit-risk of continuing treatment with Erlotinib KRKA should be carefully considered in the event of a diagnosis of keratitis. Erlotinib KRKA 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 the development of keratitis and corneal ulceration. Cases of corneal perforation or ulceration during treatment with Erlotinib KRKA have been very rarely observed (see section “Adverse reactions”).

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 Erlotinib KRKA 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 the solubility of erlotinib and, consequently, its bioavailability. It is unlikely that increasing the dose of Erlotinib KRKA when co-administered with these medicinal products will compensate for the reduced exposure. Concomitant use of Erlotinib KRKA and 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 treatment with Erlotinib KRKA, these medicinal products should be taken at least 4 hours before or 2 hours after the daily dose of Erlotinib KRKA.

Erlotinib KRKA contains lactose and therefore should not be used in patients with rare hereditary problems such as galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Disposal of unused medicine and expired medicine. Environmental contamination should be minimized. The medicine should not be disposed of via wastewater or household waste. A designated “waste collection system” 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 childbearing potential

Women of childbearing potential are advised to avoid pregnancy and to use reliable contraceptive methods during treatment with Erlotinib KRKA and for at least 2 weeks after completion 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.

Lactation

It is unknown whether erlotinib is excreted in human breast milk. No studies have been conducted to assess the effect of erlotinib on milk production or the presence of erlotinib in breast milk. As the potential for harm to the breastfed infant is unknown, breastfeeding should be avoided during treatment with Erlotinib KRKA and for at least two weeks after the last dose.

Fertility

Animal studies indicate no impairment of fertility. However, an undesirable 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; however, erlotinib use is not associated with cognitive impairment.

Method of Administration and Dosage

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

Non-small cell lung cancer (NSCLC)

Prior to initiating treatment with Erlotinib KRKA, patients with advanced or metastatic NSCLC who have not previously received chemotherapy should be tested for epidermal growth factor receptor (EGFR) mutations.

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

Pancreatic cancer

The recommended dose of Erlotinib KRKA 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 package leaflet, indication – pancreatic cancer).

If a patient does not develop rash within the first 4–8 weeks of treatment, consideration should be given to continuing Erlotinib KRKA therapy (see section "Pharmacodynamics").

If dose adjustment is required, the dose should be reduced in 50 mg decrements (see section "Special warnings and precautions for use").

Erlotinib KRKA is available in 25 mg, 100 mg, and 150 mg strengths.

Concomitant use of CYP3A4 substrates and modulators may necessitate dose adjustments (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 patients with normal liver function, caution should be exercised when administering Erlotinib KRKA to patients with hepatic insufficiency. If severe adverse reactions occur, the dose should be reduced or treatment discontinued. The safety and efficacy of Erlotinib KRKA 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 KRKA is not recommended for use in these patients (see section "Pharmacokinetics").

Renal impairment

The safety and efficacy of Erlotinib KRKA in patients with renal impairment (serum creatinine concentration 1.5 times above the 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 KRKA 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 KRKA in NSCLC patients who smoke is 300 mg. For the 300 mg dose, improved efficacy has not been demonstrated in second-line treatment after chemotherapy failure compared to the recommended 150 mg dose in patients who continue to smoke. Safety profiles 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. Patients who continue to smoke are advised to quit smoking (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use").

Children

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

Overdose

Symptoms

Single oral doses of Erlotinib KRKA up to 1000 mg in healthy volunteers and up to 1600 mg in cancer patients were tolerated. Tolerability of multiple dosing at 200 mg twice daily in healthy volunteers worsened only after several days of administration. Based on data from these studies, overdose may result in severe adverse reactions such as diarrhea, rash, and possibly elevated liver transaminase levels.

Treatment

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

Adverse reactions.

Summary of safety profile

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

Monotherapy in NSCLC

First-line treatment of patients with EGFR mutations

In an open-label, randomized Phase III study (ML20650) involving 154 patients, the safety of erlotinib was evaluated in 75 patients receiving first-line treatment for NSCLC with activating epidermal growth factor receptor (EGFR) mutations.

The most commonly observed adverse reactions were rash and diarrhea, the majority of which were of Grade 1 and 2 severity and did not require drug discontinuation. Complete information on the grade and frequency of rash and diarrhea across all clinical studies is provided in the section "Description of selected adverse reactions" below.

Maintenance therapy

In two other double-blind, randomized, placebo-controlled Phase III studies, BO18192 (SATURN) and BO25460 (IUNO), Erlotinib KRKA 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 first-line platinum-based chemotherapy. No new safety signals were identified.

The most commonly observed adverse reactions in patients treated with Erlotinib KRKA in studies BO18192 and BO25460 were rash and diarrhea.

Second- and further-line treatment

In the randomized, double-blind study BR.21 (Erlotinib KRKA administered as second-line therapy), the most commonly observed adverse reactions were rash and diarrhea, most of which were Grade 1 and 2 in severity and resolved without intervention. 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 observed adverse reactions in the pivotal study PA.3 in patients with pancreatic cancer who received erlotinib 100 mg in combination with gemcitabine were fatigue, rash, and diarrhea. Median time to onset of rash was 10 days, and to onset of diarrhea was 15 days, respectively.

Summary table of adverse reactions

The frequency of adverse reactions observed during clinical trials and post-marketing surveillance, reported with erlotinib used alone or in combination with chemotherapy, is summarized in Table 1. Adverse drug reactions are listed by MedDRA system organ class. The following criteria are used to define frequency categories: 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); and not known (cannot be estimated from available data).

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

Table 1

Summary of adverse reactions during clinical trials and post-marketing surveillance by frequency:

Infections and infestations
Very common	infections*
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 ulceration, uveitis
Respiratory, thoracic and mediastinal disorders
Very common	dyspnea, cough
Common	epistaxis
Uncommon	interstitial lung disease (ILD)*
Gastrointestinal disorders
Very common	diarrhea*, nausea, vomiting, stomatitis, abdominal pain, dyspepsia, flatulence
Common	gastrointestinal hemorrhage*
Uncommon	gastrointestinal perforations *
Rare	intestinal pneumatosis
Hepatobiliary disorders
Very common	Abnormal liver function tests*
Rare	hepatic failure*, hepatitis
Not known (cannot be estimated from available data)	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, brittle nails and nail loss, mild skin reactions such as hyperpigmentation
Rare	palmoplantar erythrodysesthesia
Very rare	Stevens-Johnson syndrome/toxic epidermal necrolysis*
Renal and urinary disorders
Common	renal failure
Uncommon	nephritis, proteinuria
General disorders
Very common	fatigue, pyrexia, chills

*For additional information, see the section "Description of individual adverse reactions" below.

Description of individual adverse reactions

Rash

Rash, including acneiform dermatitis. Rash generally presents 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, including fatal cases (see section "Special precautions").

Table 2: Summary of the frequency and severity of rash and diarrhea observed in each clinical study

Study	Indication	Rash (%)					Diarrhea (%)
		Frequency			Actions Taken		Frequency			Actions Taken
		Any	3	4	Discon.1	Dose Mod.2	Any	3	4	Discon.1	Dose Mod.2
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

1Discontinuation

2Dosage modification

Infections

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)

Including ILD with fatal outcomes in patients receiving erlotinib for the treatment of NSCLC or other progressive solid tumors (see section "Special precautions"). A higher incidence was observed in patients in Japan (see section "Special precautions").

Gastrointestinal hemorrhage

Including fatal outcomes (see section "Special precautions"). 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 included fatal outcomes (see section "Special precautions").

Abnormal liver function test results

Abnormalities included increased alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin. Cases were mainly mild or moderate in severity, transient, or associated with liver metastases.

Hepatic failure

Including fatal cases. Risk factors may include underlying liver disease or concomitant use of hepatotoxic drugs (see section "Special precautions").

Stevens-Johnson syndrome/Toxic epidermal necrolysis

Including fatal cases (see section "Special precautions").

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from moisture. No special temperature storage conditions are required for this medicinal product.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto/KRKA, d.d., Novo mesto.

KRKA-FARMA d.o.o./KRKA-FARMA d.o.o.

Manufacturer's address and location of its business operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

V. Holjevca 20/E, 10450 Jastrebarsko, Croatia/V. Holjevca 20/E, 10450 Jastrebarsko, Croatia.